Fact-checked by Grok 2 weeks ago

Signal transduction

Signal transduction is the biochemical process by which cells detect and respond to external signals, converting extracellular stimuli such as hormones, growth factors, or neurotransmitters into intracellular responses that regulate cellular functions like proliferation, differentiation, and metabolism.^[1] This process typically begins with the binding of a signaling molecule, or ligand, to a specific receptor on the cell surface or within the cell, initiating a cascade of molecular events that amplify and propagate the signal.^[2] Key components include receptors (e.g., G protein-coupled receptors [GPCRs], receptor tyrosine kinases [RTKs]), second messengers (e.g., cyclic AMP [cAMP], calcium ions [Ca²⁺]), and effector proteins such as kinases that modify target molecules through phosphorylation.^[1] Major signal transduction pathways encompass several conserved mechanisms across eukaryotes. For instance, the GPCR pathway involves ligand binding that activates heterotrimeric G proteins, leading to the production of second messengers like cAMP, which activate protein kinase A (PKA) to influence downstream targets including transcription factors.^[2] In contrast, RTK pathways, activated by growth factors, trigger autophosphorylation and recruitment of adaptor proteins like Ras, initiating the mitogen-activated protein kinase (MAPK) cascade that culminates in nuclear gene expression changes.^[1] Other notable pathways include those mediated by cytokine receptors via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) system, and non-receptor pathways like the Wnt or Notch signaling, which are crucial for developmental processes.^[2] Signal transduction is fundamental to multicellular organismal physiology, enabling coordinated responses to environmental cues and intercellular communication. Dysregulation of these pathways contributes to numerous diseases, including cancers (e.g., via aberrant RTK signaling), autoimmune disorders (e.g., through dysregulated JAK-STAT), and metabolic conditions like diabetes.^[2] Advances in understanding these mechanisms have led to targeted therapies, such as tyrosine kinase inhibitors for oncology and monoclonal antibodies against GPCRs. Recent research emphasizes the role of spatial organization, feedback loops, and integration of multiple signals for robust cellular decision-making.^[3]

Introduction

Definition and process overview

Signal transduction is the process by which cells detect and respond to external stimuli, converting extracellular signals into intracellular responses through a series of coordinated biochemical reactions. This involves the transmission of molecular signals from the cell's exterior to its interior, typically initiated by the binding of a signaling molecule to a receptor, which triggers cascades that relay and amplify the signal to elicit a specific cellular outcome.^[4]^[5] The general process of signal transduction follows a stepwise sequence. First, an extracellular stimulus binds to a specific receptor, inducing a conformational change in the receptor that activates intracellular effectors. This activation propagates the signal through relay mechanisms, such as enzymatic modifications or molecular interactions, leading to the engagement of downstream components that produce the cellular response, such as changes in gene expression or metabolic activity. The process concludes with termination mechanisms, including feedback inhibition, enzymatic reversal of modifications, or degradation of signaling components, to restore the cell to its basal state and prevent prolonged activation.^[4]^[5] A basic overview of the process can be described as a linear flowchart: stimulus detection (ligand binds receptor) → receptor activation (conformational change) → effector engagement (intracellular relay) → response generation (cellular adaptation) → signal termination (deactivation). Specificity in signal transduction is maintained by the high affinity and selectivity of receptor-ligand interactions, which ensure precise signal detection, and by spatial compartmentalization within signaling complexes, which limits cross-talk between pathways.^[4]^[6]

Biological significance

Signal transduction is fundamental to cellular function, enabling cells to sense environmental cues and initiate appropriate responses that maintain homeostasis and support organismal viability. By converting extracellular signals into intracellular events, such as alterations in gene expression, metabolic activity, and cytoskeletal dynamics, these pathways ensure adaptive responses to stimuli like nutrients, hormones, and stress factors.^[2] This process is crucial for preserving ionic and metabolic balance, as seen in feedback mechanisms that regulate calcium levels and energy metabolism across cell types.^[7] In multicellular organisms, signal transduction coordinates intercellular communication, allowing synchronized activities that underpin tissue integrity and physiological regulation.^[2] At varying scales, signal transduction influences outcomes from individual cells to entire organisms. At the single-cell level, it drives rapid responses, such as the opening of ion channels in neurons to propagate electrical signals for synaptic transmission.^[8] On a tissue scale, hormone signaling, like insulin-mediated glucose uptake, orchestrates coordinated metabolic adjustments across organs to sustain energy homeostasis.^[2] These pathways also facilitate developmental coordination, guiding cell proliferation, differentiation, and morphogenesis during embryogenesis and organ formation in multicellular systems.^[8] Evolutionarily, signal transduction serves as a hub for innovation, with conserved modules like receptor tyrosine kinase (RTK) pathways, with components appearing in early eukaryotes such as choanoflagellates, and Wnt signaling, which emerged in early metazoans, persisting across species to vertebrates.^[8]^[9] This conservation reflects modular architectures—such as Ras GTPases and SH2 domains—that enable pathway crosstalk and adaptability, driving diversification through gene duplication and domain shuffling.^[8] Dysregulation of these pathways, often via mutations in oncogenes like EGFR, disrupts normal controls and promotes uncontrolled proliferation, a hallmark of cancers such as those driven by aberrant MAPK signaling.^[10]

Stimuli

Chemical stimuli

Chemical stimuli in signal transduction encompass a diverse array of molecular signals, primarily ligands, that trigger cellular responses by interacting with specific receptors on or within target cells. These ligands include hormones, such as insulin, which regulate metabolic processes like glucose uptake in tissues; neurotransmitters, exemplified by acetylcholine, which mediate rapid synaptic transmission in the nervous system; and cytokines, including interleukins, which coordinate immune responses by promoting inflammation or cell proliferation.^[11]^[12] Such chemical signals enable precise communication between cells, converting extracellular cues into intracellular events that govern physiological functions.^[13] The sources of these chemical stimuli vary based on the spatial range of signaling. In autocrine signaling, a cell secretes ligands that bind to receptors on its own surface, allowing self-regulation, as seen with certain growth factors in tumor cells. Paracrine signaling involves ligands diffusing short distances to affect neighboring cells, such as nitric oxide modulating vascular tone in adjacent smooth muscle cells. Endocrine signaling, in contrast, employs hormones released into the bloodstream to reach distant target organs, like thyroid hormones influencing metabolism across the body.^[13]^[2] These modes ensure efficient signal propagation tailored to the biological context.^[14] Specificity in chemical signaling arises from ligand concentration gradients and binding affinities to receptors, which dictate the strength and selectivity of the response. For example, in local paracrine environments, steep concentration gradients limit signal spread, ensuring targeted effects on nearby cells without widespread activation. Binding affinities, often in the nanomolar range for hormones like insulin, further refine this selectivity by favoring high-affinity interactions under physiological conditions.^[13] A notable case involves steroid hormones, such as cortisol, which, due to their lipophilic nature, passively diffuse across plasma membranes to directly engage intracellular receptors, bypassing surface binding.^[12]

Physical stimuli

Physical stimuli encompass non-chemical environmental cues, such as mechanical forces, temperature variations, light, and osmolarity changes, that initiate signal transduction pathways in cells to elicit adaptive responses. These stimuli are detected by specialized sensors that convert physical inputs into biochemical signals, often through rapid alterations in membrane potential or ion concentrations. Unlike chemical ligands, physical stimuli typically trigger immediate cellular adjustments to maintain homeostasis or respond to environmental pressures.^[15] Mechanical forces represent a primary class of physical stimuli, including shear stress from fluid flow in blood vessels, tensile strain in tissues, and pressure changes. In vascular endothelium, laminar shear stress (approximately 10-50 dyn/cm²) is sensed to regulate vascular remodeling and prevent atherosclerosis. Detection occurs via mechanosensitive ion channels like Piezo1 and Piezo2, which open in response to membrane deformation, allowing influx of cations such as Ca²⁺ to activate downstream signaling. Integrins also serve as sensors for extracellular matrix stiffness and tensile forces, facilitating touch sensation in skin cells by linking mechanical cues to cytoskeletal rearrangements. These mechanisms often couple to rapid ion fluxes, enabling quick responses like cell migration or proliferation.^[16]^[17]^[18] Temperature changes, particularly heat shock, act as another key physical stimulus, inducing the heat shock response (HSR) to protect against protein denaturation. Elevated temperatures (e.g., above 42°C) are detected through heat shock factor 1 (HSF1), which trimerizes and binds to promoters of heat shock protein (HSP) genes, promoting chaperone production for thermotolerance. In some cases, high Ca²⁺ levels associated with temperature-induced membrane perturbations contribute to HSF1 activation, linking thermal sensing to ion-mediated signaling. This pathway exemplifies how physical stimuli drive rapid protective responses without relying on ligand binding.^[19] Light serves as a physical stimulus in phototransduction, primarily in sensory cells like retinal rods and cones, where photons trigger electrical signals for vision. Photoreceptors, such as opsin-based rhodopsin, absorb light to undergo conformational changes, activating G-protein cascades that modulate cyclic nucleotide-gated channels. In vertebrate rods, this leads to cGMP hydrolysis and channel closure, hyperpolarizing the cell with high sensitivity (detecting single photons). Photoreceptors also entrain circadian rhythms by influencing clock gene expression in response to light-dark cycles. The process highlights rapid ion flux coupling, as Na⁺ and Ca²⁺ movements alter membrane potential almost instantaneously. Receptor activation here initiates these cascades, as detailed in receptor-specific sections.^[20]^[21] Osmolarity gradients, arising from hypo- or hypertonic environments, constitute physical stimuli that alter cell volume and trigger osmosensing pathways. Hyperosmotic stress (e.g., ≥405 mosmol/L) is detected by endosomal acidification and stretch-activated channels, leading to reactive oxygen species (ROS) production and activation of p38 MAPK for adaptation.^[22]^[23]^[24]^[25] In mammalian cells, integrins sense hypotonic swelling, coupling to Src kinases and ion channels for volume regulation via osmolyte uptake. These sensors facilitate rapid Ca²⁺ influx, enabling immediate responses like apoptosis prevention or proliferation in osmotically challenged tissues such as the kidney.^[22]^[23]^[24]

Receptors

Cell surface receptors

Cell surface receptors are integral membrane proteins embedded in the plasma membrane that detect extracellular signals, such as hormones, neurotransmitters, and growth factors, and transduce them into intracellular responses. These receptors are essential for cells to respond to hydrophilic ligands that cannot readily cross the lipid bilayer, distinguishing them from intracellular receptors that handle lipophilic signals within the cell. Typically, they feature an extracellular domain for ligand binding, a transmembrane domain anchoring the protein, and an intracellular domain that initiates signaling cascades upon activation.^[26] The major types of cell surface receptors include G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), ligand-gated ion channels, integrins, and Toll-like receptors (TLRs). GPCRs, the largest family, consist of seven transmembrane helices and couple to heterotrimeric G proteins to modulate second messengers like cyclic AMP; the human genome encodes approximately 800 GPCRs, many of which mediate sensory functions such as vision (e.g., rhodopsin) and smell (e.g., olfactory receptors). RTKs possess an extracellular ligand-binding domain and an intracellular kinase domain; upon ligand binding, they undergo dimerization and autophosphorylation on tyrosine residues, recruiting adaptor proteins to propagate signals. Ligand-gated ion channels, such as nicotinic acetylcholine receptors, form pores that open in response to ligand binding, allowing rapid ion flux (e.g., Na⁺ or Ca²⁺) to depolarize the membrane and trigger immediate responses. Integrins are heterodimeric adhesion receptors (α and β subunits) that bind extracellular matrix components like fibronectin, facilitating bidirectional signaling that regulates cell migration, adhesion, and survival through pathways involving focal adhesion kinase. TLRs, type I transmembrane proteins with leucine-rich extracellular domains and Toll/IL-1 receptor (TIR) intracellular domains, recognize pathogen-associated molecular patterns (e.g., lipopolysaccharide via TLR4) to activate innate immune responses via adaptor proteins like MyD88.^[26]^[27]^[28]^[29]^[26]^[30]^[31] Activation of cell surface receptors generally involves ligand binding to the extracellular domain, which induces a conformational change or promotes oligomerization, such as dimerization in RTKs or clustering in integrins, enabling the intracellular domain to recruit and activate downstream effectors like kinases or G proteins. For GPCRs and TLRs, this often leads to heterotrimeric protein dissociation or adaptor recruitment, respectively, without enzymatic activity in the receptor itself. In ligand-gated channels, activation directly alters channel gating for ion permeation. These initial steps ensure specificity and amplify the signal for cellular decision-making.^[26]^[29]^[31]

Intracellular receptors

Intracellular receptors are proteins located within the cell that detect lipophilic or diffusible signaling molecules, enabling direct modulation of intracellular processes without requiring membrane-bound intermediaries. Unlike cell surface receptors that respond to hydrophilic ligands via extracellular binding, intracellular receptors often bind signals that penetrate the plasma membrane, such as steroid hormones or metabolites, to initiate rapid or targeted responses. These receptors play crucial roles in hormone action, metabolic regulation, and stress responses by integrating signals into transcriptional or enzymatic outputs. The primary examples are nuclear receptors, which function as ligand-activated transcription factors.^[26] Nuclear receptors are classified into two main types within the superfamily. Type I nuclear receptors, such as the estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), mineralocorticoid receptor (MR), and glucocorticoid receptor (GR), are located in the cytoplasm in their inactive state. Structurally, they consist of an N-terminal domain (NTD) containing activation function 1 (AF-1) for transcriptional activation, a central DNA-binding domain (DBD) with two zinc finger motifs for sequence-specific DNA recognition, a hinge region with a nuclear localization signal (NLS), and a C-terminal ligand-binding domain (LBD) incorporating activation function 2 (AF-2). The GR, a prototypical example first cloned in 1985, binds glucocorticoids like cortisol, which diffuse across the cell membrane to reach cytoplasmic receptors. Upon ligand binding, type I receptors undergo a conformational change that dissociates inhibitory chaperones such as heat shock protein 90 (HSP90), promoting dimerization, nuclear translocation, and binding to hormone response elements (HREs) on DNA to modulate transcription. This direct genomic pathway allows steroid hormones to exert precise control over processes like metabolism and inflammation through the GR's homodimeric action.^[32]^[26] Type II nuclear receptors, in contrast, are primarily located in the nucleus even without ligand and include the thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR), and peroxisome proliferator-activated receptors (PPARs). These receptors often heterodimerize with retinoid X receptors (RXRs) and bind to response elements in the presence of ligands like thyroid hormones (T3/T4), retinoic acid, vitamin D, or fatty acid derivatives. Ligand binding induces conformational changes that recruit coactivators or corepressors to regulate gene expression, influencing development, differentiation, and metabolic homeostasis. Unlike type I, type II receptors can repress transcription in the apo form and activate upon ligand binding, providing a mechanism for fine-tuned responses to lipophilic signals.^[26]

Signal Transduction Mechanisms

Second messenger systems

Second messenger systems involve small, diffusible molecules or ions that transmit signals from activated cell surface receptors to intracellular targets, enabling rapid amplification and propagation of the initial stimulus within the cell. These intermediaries, often generated enzymatically in response to receptor activation, diffuse through the cytosol or remain membrane-associated to modulate effector proteins such as enzymes and ion channels. Unlike direct protein-protein interactions at the receptor, second messengers allow for spatial and temporal control of signaling, ensuring specificity in diverse cellular contexts.^[33] Among the primary types of second messengers are cyclic adenosine monophosphate (cAMP), inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG), calcium ions (Ca²⁺), and various lipid-derived molecules such as phosphatidylinositol derivatives. cAMP is synthesized from ATP by the enzyme adenylyl cyclase, which is activated upon G protein-coupled receptor (GPCR) stimulation; this process converts the extracellular signal into an intracellular one that binds and activates protein kinase A (PKA). Similarly, IP3 and DAG are produced by phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane following receptor tyrosine kinase or GPCR activation; IP3 diffuses to the endoplasmic reticulum to trigger Ca²⁺ release, while DAG remains membrane-bound to recruit and activate protein kinase C (PKC). Calcium ions serve as a ubiquitous second messenger, with transient elevations in cytosolic concentration orchestrating a wide array of responses by binding to proteins like calmodulin, which in turn activates calcium/calmodulin-dependent protein kinases (CaMKs). Lipid messengers, including phosphatidylinositol 3,4,5-trisphosphate (PIP3) generated by phosphoinositide 3-kinase (PI3K), facilitate signaling by recruiting pleckstrin homology domain-containing proteins to specific membrane locales.^[33]^[34]^[35] The generation of these second messengers is tightly coupled to receptor activation, ensuring that signaling is both stimulus-specific and transient. For instance, upon ligand binding to a GPCR, the associated heterotrimeric G protein exchanges GDP for GTP, stimulating adenylyl cyclase to produce cAMP, which then dissociates PKA into regulatory and catalytic subunits, allowing the latter to phosphorylate downstream targets and amplify the signal. In the IP3/DAG pathway, PLC activation cleaves PIP2 into IP3, which binds IP3 receptors on intracellular stores to mobilize Ca²⁺, creating oscillatory waves that propagate the signal; concurrently, DAG potentiates PKC activity in a Ca²⁺-dependent manner. These enzymatic steps provide a checkpoint for regulation, with second messenger levels controlled by degradative enzymes like phosphodiesterases for cAMP or phosphatases for lipids, preventing prolonged activation.^[33]^[36] Calcium stands out as a versatile second messenger due to its ability to integrate multiple signaling inputs and elicit diverse responses across cell types. Upon release from intracellular stores via IP3 or entry through plasma membrane channels, Ca²⁺ binds calmodulin, inducing a conformational change that exposes binding sites for target kinases such as CaMKII, which autophosphorylates to sustain activity and regulate processes like synaptic plasticity in neurons. This binding mechanism allows Ca²⁺ to function at low micromolar concentrations, with its signaling decoded by the kinetics of concentration changes—spikes for fast responses or sustained elevations for gene expression. The universality of Ca²⁺ signaling underscores its evolutionary conservation, from prokaryotes to mammals, highlighting its role in coordinating contraction, secretion, and proliferation.^[33] To maintain signaling fidelity, second messengers are subject to compartmentalization, which restricts their diffusion and ensures localized activation of effectors. For cAMP, A-kinase-anchoring proteins (AKAPs) tether PKA to specific subcellular sites near adenylyl cyclase, creating microdomains where cAMP gradients drive precise responses without global spillover. Similarly, Ca²⁺ signaling is confined to nanodomains via buffering proteins and pumps, preventing non-specific activation of distant targets and allowing simultaneous encoding of multiple signals. Lipid messengers like DAG and PIP3 are inherently compartmentalized within membrane rafts or scaffolds, further enhancing specificity. This spatial organization is crucial for preventing crosstalk and enabling cells to process complex environmental cues efficiently.^[33]^[37]

Phosphorylation-based cascades

Phosphorylation-based cascades represent a core mechanism in signal transduction, involving sequential covalent modifications of proteins that propagate extracellular signals into intracellular responses. In these cascades, protein kinases transfer a phosphate group from adenosine triphosphate (ATP) to hydroxyl-containing amino acids—primarily serine, threonine, or tyrosine—on substrate proteins, altering their conformation, activity, subcellular localization, or binding affinities. This process is highly specific, with kinases recognizing consensus sequences on targets to ensure precise signal routing. The reaction is enzymatic and catalytic, enabling one kinase molecule to modify numerous substrates efficiently.^[38] The reversibility of phosphorylation is maintained by protein phosphatases, which hydrolyze the phosphate ester bond to return proteins to their basal state, creating dynamic on-off switches that underpin temporal control in signaling. Phosphorylation often induces allosteric changes, leading to ultrasensitive, switch-like responses where small input signals yield sharp, digital-like outputs in kinase activity. This binary regulation contrasts with graded responses in other systems and allows cells to achieve threshold-dependent decision-making in processes like proliferation and differentiation. A simplified representation of the phosphorylation reaction is:

\text{Protein kinase} + \text{ATP} + \text{Substrate} \rightarrow \text{Phospho-substrate} + \text{ADP} + \text{Protein kinase}

This cycle facilitates rapid signal propagation without depleting kinase pools.90121-0)^[38] Prominent examples of phosphorylation cascades include mitogen-activated protein kinase (MAPK) modules, such as the extracellular signal-regulated kinase (ERK) pathway, where a three-tiered kinase sequence—MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK—relays signals through sequential activations, culminating in ERK-mediated gene expression changes. Another key cascade is the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, in which receptor-bound JAK kinases autophosphorylate and then phosphorylate cytoplasmic STAT proteins, promoting their dimerization, nuclear entry, and transcriptional activation. These cascades amplify signals, as each activated kinase can phosphorylate multiple downstream targets, potentially generating exponential gains in response intensity across tiers—for instance, one active MAP3K may activate several MAP2Ks, each of which in turn phosphorylates numerous MAPKs. Such amplification ensures robust transduction even from weak stimuli, while scaffolding proteins and feedback loops fine-tune specificity and duration. Second messengers may briefly activate initiating kinases in these cascades.^[39]

Signal Processing

Amplification and sensitivity

Signal transduction pathways often achieve amplification through cascading enzymatic reactions where a single activated molecule triggers the activation of numerous downstream effectors, thereby magnifying the initial signal. For instance, in G protein-coupled receptor (GPCR) signaling, one ligand-bound receptor can catalyze the GDP-GTP exchange on multiple Gα subunits, leading to the activation of several G proteins and subsequent production of many second messenger molecules like cAMP. This process ensures that even weak stimuli can elicit robust cellular responses, as demonstrated in studies of adrenergic signaling where a single receptor activation can generate thousands of cAMP molecules.^[40] Sensitivity in signal transduction is enhanced by mechanisms that allow cells to detect and respond to low concentrations of stimuli with high precision, often through ultrasensitive switches in kinase cascades. In mitogen-activated protein kinase (MAPK) pathways, for example, the multi-step phosphorylation process exhibits ultrasensitivity, characterized by a Hill coefficient greater than 1, which produces a sigmoidal response curve and enables switch-like, all-or-nothing activation rather than gradual changes. This property, first quantified in models of the yeast cell cycle and fission yeast MAPK cascades, allows cells to establish sharp thresholds for decision-making, such as in proliferation or differentiation.^[41]^[42] Feedback loops further refine amplification and sensitivity by modulating response dynamics, often through negative feedback that sharpens signaling precision and prevents overstimulation. In receptor tyrosine kinase (RTK) pathways, rapid negative feedback via phosphatases or induced inhibitors, such as in the epidermal growth factor receptor system, leads to desensitization and pulse-like responses that enhance temporal resolution. These loops ensure adaptive tuning, as seen in bacterial chemotaxis where feedback maintains sensitivity across varying stimulus intensities.^[43] At a conceptual level, signal transduction can operate in analog or digital modes, influencing how amplification and sensitivity are perceived. Analog signaling involves proportional, graded responses, while digital signaling produces binary, all-or-nothing outputs, as in voltage-gated ion channels where depolarization triggers abrupt calcium influx for decisive events like neurotransmitter release. This dichotomy allows cells to balance fine-tuned sensitivity with decisive amplification in contexts like synaptic transmission.

Integration and crosstalk

In signal transduction, integration refers to the process by which cells combine inputs from multiple signaling pathways to generate coordinated and context-specific responses, while crosstalk describes the interactions between these pathways through shared components or regulatory mechanisms. This allows cells to process complex environmental cues rather than responding to isolated signals, enabling adaptive behaviors such as proliferation in favorable conditions or survival under duress. For instance, the mitogen-activated protein kinase (MAPK) pathway, which promotes cell growth and differentiation, frequently intersects with the phosphoinositide 3-kinase (PI3K)-Akt pathway, which supports cell survival and metabolism; these pathways share upstream activators like Ras and can mutually regulate downstream effectors, such as through Akt-mediated inhibition of MAPK signaling to fine-tune proliferative responses.^[44]^[45] Scaffold proteins play a central role in signal integration by organizing multiprotein complexes that localize and coordinate enzymes from different pathways, thereby enhancing specificity and efficiency. A-kinase anchoring proteins (AKAPs), for example, tether protein kinase A (PKA) along with phosphatases, phosphodiesterases, and other kinases to specific subcellular sites, such as the plasma membrane or mitochondria, allowing localized cAMP-dependent signaling to intersect with calcium or growth factor pathways without global interference. This compartmentalization prevents aberrant activation and ensures that integrated signals produce precise outcomes, like targeted phosphorylation events in response to concurrent stimuli.^[46]^[47] Such integration and crosstalk enable context-dependent cellular responses, where the combination of signals dictates the outcome; for example, growth factors like epidermal growth factor (EGF) typically drive proliferation via receptor tyrosine kinases, but when paired with stress signals such as UV irradiation activating JNK (a MAPK subfamily), the response shifts toward apoptosis or cell cycle arrest to protect tissue integrity. Network motifs, recurrent wiring patterns in signaling networks, further contribute to this robustness; feedforward loops (FFLs), one of the most common motifs, allow rapid activation of responses while providing delays or filters for noise, as seen in MAPK cascades where an input directly and indirectly influences an output to ensure reliable signal propagation amid varying inputs. Coherent FFLs, in particular, accelerate signal onset and desensitize to persistent stimuli, promoting adaptive integration across pathways.^[48]^[49]

Cellular Responses

Immediate cellular changes

Immediate cellular changes in signal transduction encompass rapid, non-genomic responses that occur within seconds to minutes, enabling cells to quickly adapt to extracellular signals without altering gene expression.^[1] These changes are typically mediated by second messengers such as cyclic AMP (cAMP) or calcium ions (Ca²⁺), which propagate the signal intracellularly and trigger post-translational modifications that are often reversible upon signal cessation.^[1] Unlike slower long-term adaptations involving transcriptional regulation, these immediate effects focus on direct modulation of existing cellular machinery to produce functional outcomes.^[50] One primary type of immediate response is the modulation of ion channels, where ligand binding rapidly alters membrane permeability to ions, leading to changes in membrane potential. For instance, neurotransmitter binding to ligand-gated ion channels, such as nicotinic acetylcholine receptors, induces depolarization by allowing influx of cations like Na⁺ and Ca²⁺, facilitating synaptic transmission in neurons.^[51] This process occurs on a millisecond to second timescale and is essential for fast excitatory responses in excitable cells.^[52] Cytoskeletal rearrangements represent another key immediate change, involving dynamic polymerization and depolymerization of actin filaments or microtubules in response to signaling cascades. These alterations, often triggered by Rho GTPases or Ca²⁺-dependent pathways, enable rapid cellular processes like shape changes, motility, or vesicle trafficking, occurring within seconds to minutes.^[53] For example, in migrating cells, signal-induced activation of actin-binding proteins leads to lamellipodia formation, supporting directional movement.^[54] Enzyme activation provides a further mechanism for immediate responses, where second messengers phosphorylate or allosterically regulate enzymes to alter metabolic flux. A classic case is the cAMP-mediated activation of protein kinase A (PKA), which phosphorylates phosphorylase kinase, ultimately activating glycogen phosphorylase to initiate glycogen breakdown and glucose release in liver and muscle cells.^[55] This cascade unfolds in seconds, providing rapid energy mobilization during stress.^[1] Representative examples of these changes include Ca²⁺-induced muscle contraction, where signal-evoked release of Ca²⁺ from the sarcoplasmic reticulum binds to troponin, enabling actin-myosin interactions and force generation within milliseconds to seconds.^[56] Similarly, in endocrine cells, elevated cytosolic Ca²⁺ triggers exocytosis of hormone-containing vesicles, as seen in insulin secretion from pancreatic β-cells, occurring on a timescale of seconds to promote rapid physiological adjustments.^[57] These responses underscore the efficiency of second messenger systems in translating signals into immediate, reversible cellular actions.^[1]

Long-term adaptations

Long-term adaptations in signal transduction refer to sustained cellular responses that occur over timescales of hours to days, primarily through alterations in gene expression and cellular reprogramming. These adaptations enable cells to maintain changes in function or phenotype in response to persistent signaling cues, contrasting with transient immediate effects by committing to heritable modifications in cellular behavior. A key mechanism underlying these adaptations is transcriptional regulation, where signaling pathways activate transcription factors that bind to specific DNA sequences to modulate gene expression. For instance, the cAMP response element-binding protein (CREB) is phosphorylated by protein kinase A in response to cAMP signaling, leading to its activation and subsequent induction of genes involved in processes like long-term memory formation in neurons.^[58] This activation exemplifies how initial signaling cascades can trigger delayed transcriptional programs that sustain adaptive changes. Long-term adaptations also encompass cell proliferation and differentiation, where sustained signaling promotes cell cycle progression or lineage commitment. In proliferation, pathways such as those involving mitogen-activated protein kinases (MAPKs) drive the expression of cyclins and other regulators, allowing cells to undergo multiple divisions in response to growth factors over extended periods. Differentiation, meanwhile, involves the reprogramming of gene expression profiles to establish specialized cell fates, often coordinated by signaling gradients that persist for days. Nuclear receptors play a central role in these processes by directly interacting with chromatin to regulate transcription. These ligand-activated transcription factors, such as the estrogen receptor, translocate to the nucleus upon binding their ligands and recruit coactivators to modify gene promoters, thereby altering chromatin structure and facilitating long-term gene activation or repression.^[59] For example, the estrogen receptor binds to estrogen response elements on DNA, leading to histone acetylation and enhanced transcription of target genes involved in cellular adaptation. Epigenetic modifications further ensure the durability of these adaptations by imposing lasting changes on chromatin without altering the DNA sequence. Histone phosphorylation, for instance, is induced by signaling kinases like MAPK or Aurora B, which mark histones for remodeling and maintain open chromatin states that support prolonged gene expression during proliferation or differentiation.^[60] Such modifications allow cells to "remember" prior signaling events, enabling adaptive responses that persist beyond the initial stimulus.^[60]

Key Signaling Pathways

G protein-coupled receptor pathways

G protein-coupled receptors (GPCRs) constitute the largest superfamily of integral membrane proteins dedicated to signal transduction, enabling cells to detect and respond to diverse extracellular ligands including hormones, neurotransmitters, peptides, and sensory stimuli such as photons and odors. These receptors feature a characteristic seven-transmembrane α-helical bundle architecture, with an extracellular N-terminus for ligand recognition and an intracellular C-terminus for effector interactions. Upon agonist binding, GPCRs transition from an inactive to an active conformation, primarily through outward movement of transmembrane helix 6, which exposes a binding pocket for intracellular transducers.^[61]^[62] The core of GPCR signaling involves activation of heterotrimeric guanine nucleotide-binding proteins (G proteins), composed of α, β, and γ subunits, which anchor to the plasma membrane via lipid modifications. In the basal state, the Gα subunit binds guanosine diphosphate (GDP) and associates tightly with the Gβγ dimer, rendering the complex inactive. Ligand-induced conformational changes in the GPCR catalyze the exchange of GDP for guanosine triphosphate (GTP) on Gα, promoting dissociation of the heterotrimer into Gα-GTP and free Gβγ, both of which can modulate downstream effectors until intrinsic GTPase activity on Gα hydrolyzes GTP to GDP, allowing reassociation and signal termination. This activation process can be schematically represented as:

\text{Ligand} + \text{GPCR} \rightleftharpoons \text{GPCR-ligand complex} \quad \xrightarrow{\text{G protein}} \text{G}_\alpha\text{-GTP} + \text{G}_{\beta\gamma}

The GPCR acts as a guanine nucleotide exchange factor (GEF) in this relay, amplifying the signal through rapid cycling.^[61]^[62] G proteins diversify GPCR outputs into distinct biochemical cascades based on the Gα subtype. The stimulatory Gαs subfamily activates adenylyl cyclase isoforms, elevating intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn activates protein kinase A to phosphorylate targets involved in processes like glycogenolysis and gene expression; representative ligands include epinephrine acting on β-adrenergic receptors. Conversely, the inhibitory Gαi/o subfamily suppresses adenylyl cyclase activity, reducing cAMP production and dampening similar pathways, as seen with opioid or muscarinic receptor activation. The Gαq/11 subfamily stimulates phospholipase C-β (PLC-β), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG); IP₃ mobilizes Ca²⁺ from endoplasmic reticulum stores via IP₃ receptors, while DAG recruits and activates protein kinase C at the membrane, influencing contraction, secretion, and proliferation. These branches allow GPCRs to fine-tune cellular responses across physiological contexts, from vision (rhodopsin coupled to Gαt) to olfaction (various Gαolf).^[61] Reflecting their central role in physiology and pathology, GPCRs are prominent therapeutic targets, with approximately 35% of all U.S. Food and Drug Administration (FDA)-approved drugs acting on these receptors as of 2017, including agonists, antagonists, and allosteric modulators for conditions ranging from hypertension to psychiatric disorders. This druggability stems from the receptors' accessibility and the specificity of their signaling branches, though challenges persist in selectively targeting biased agonism or Gβγ-mediated effects.^[63]

Receptor tyrosine kinase pathways

Receptor tyrosine kinases (RTKs) are transmembrane proteins that play a central role in signal transduction for cell growth, differentiation, and survival, responding to extracellular ligands such as growth factors. Upon ligand binding, RTKs undergo conformational changes that promote receptor dimerization, a critical step for activation. This dimerization brings the intracellular kinase domains into close proximity, enabling trans-autophosphorylation of specific tyrosine residues in the cytoplasmic tail.^[64] The autophosphorylation creates docking sites for downstream signaling molecules containing Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domains, such as adaptor proteins Grb2 and Shc. These adaptors recruit and activate guanine nucleotide exchange factors (GEFs) like Sos, which in turn stimulate the Ras GTPase. Activated Ras then initiates the mitogen-activated protein kinase (MAPK) cascade, involving sequential phosphorylation of Raf, MEK, and ERK kinases, ultimately driving gene expression for cell proliferation. Concurrently, phosphotyrosines recruit the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to the production of PIP3 and activation of Akt (also known as PKB), which promotes cell survival by inhibiting apoptosis through targets like Bad and FoxO transcription factors.^[64]^[65] The activation process can be schematically represented as:

$2 \text{RTK} + \text{Ligand} \rightarrow (\text{RTK-Ligand})_2 \rightarrow \text{p-Tyr sites recruiting adaptors}

This model illustrates the ligand-induced dimerization and subsequent phosphorylation events that propagate signals.^[64] A prominent example is the epidermal growth factor receptor (EGFR), an RTK whose mutations, particularly in the kinase domain, constitutively activate these pathways and drive approximately 10-15% of non-small cell lung cancers, especially in non-smokers and certain ethnic populations.^[66]^[65]

Applications and Dysregulation

Physiological roles

Signal transduction plays essential roles in maintaining physiological homeostasis and coordinating organismal functions across multicellular organisms. At the cellular level, it enables the integration of environmental cues to drive adaptive responses, such as sensory perception, metabolic regulation, and developmental patterning. For instance, in sensory perception, G protein-coupled receptors (GPCRs) like rhodopsin in rod cells of the retina convert light stimuli into electrical signals, initiating a cascade that propagates visual information to the brain.^[61] This process exemplifies how signal transduction amplifies weak external signals for precise detection, ensuring survival through rapid environmental awareness.^[67] In metabolic homeostasis, insulin signaling exemplifies signal transduction's role in regulating energy balance. Upon binding to its receptor tyrosine kinase (RTK), insulin activates the PI3K-Akt pathway, promoting glucose transporter 4 (GLUT4) translocation to the cell membrane in muscle and adipose tissues, thereby facilitating glucose uptake and preventing hyperglycemia.^[68] This mechanism maintains blood glucose levels within a narrow range, supporting systemic energy distribution and preventing metabolic imbalances. Similarly, during embryonic development, the Wnt/β-catenin pathway orchestrates cell fate decisions and tissue morphogenesis; for example, Wnt ligands stabilize β-catenin, which translocates to the nucleus to activate genes involved in axis formation and organogenesis.^[69] These pathways ensure coordinated growth and differentiation, foundational to organismal development.^[70] At the organismal level, signal transduction coordinates complex responses in immunity, neurotransmission, and reproduction. In the immune system, cytokine receptors trigger JAK-STAT and MAPK pathways in leukocytes, enabling rapid coordination of innate and adaptive responses, such as T-cell activation and inflammation resolution, to defend against pathogens.^[71] Neurotransmission relies on neurotransmitter binding to ionotropic and metabotropic receptors, initiating second messenger cascades like cAMP production or calcium influx, which modulate synaptic plasticity and propagate neural signals across the nervous system.^[72] In reproduction, gonadotropin-releasing hormone (GnRH) signaling via GPCRs in the pituitary drives gonadotropin release, regulating gametogenesis and ovulation through downstream cascades that synchronize hormonal and cellular events.^[73] A key example of direct cell-cell communication is the Notch pathway, where ligand-receptor interactions on adjacent cells release the Notch intracellular domain, promoting lateral inhibition and precise tissue patterning during organ formation.^[74] The physiological significance of these pathways is underscored by their evolutionary conservation. Core signaling modules, such as those involving RTKs, trace back to simpler organisms; while yeast lack true RTKs, their mating pheromone response employs analogous MAPK cascades that parallel human RTK-driven growth signaling, highlighting how ancient transduction mechanisms have been repurposed for complex metazoan functions like development and homeostasis.^[75] This conservation ensures robust, adaptable physiological roles across species.

Pathological consequences

Dysregulation of signal transduction pathways contributes significantly to various diseases by disrupting normal cellular communication and response mechanisms. In cancer, alterations in these pathways are a hallmark feature, enabling uncontrolled proliferation and survival. For instance, mutations in the BRAF gene, particularly the V600E variant, constitutively activate the MAPK/ERK signaling cascade, promoting oncogenesis in melanomas and other malignancies. Such overactive pathways are prevalent, with genetic changes in signaling components observed in the vast majority of tumors across cancer types. Targeted therapies have emerged to counteract these defects; imatinib, for example, specifically inhibits the BCR-ABL fusion tyrosine kinase in chronic myeloid leukemia, transforming a previously fatal disease into a manageable condition. More recent advances as of 2025 include PI3K inhibitors like alpelisib for PIK3CA-mutated breast cancer and KRAS G12C inhibitors such as sotorasib for non-small cell lung cancer, which target dysregulated RTK and MAPK pathways to improve outcomes in specific subtypes.^[76] In metabolic disorders like type 2 diabetes, signal transduction impairments lead to insulin resistance, where defective insulin receptor signaling fails to adequately activate downstream pathways such as PI3K/AKT, impairing glucose uptake in target tissues. This dysregulation often stems from mechanisms including chronic stimulation from persistent ligands like inflammatory cytokines, and loss of negative feedback loops that normally attenuate signaling to prevent overload. For example, serine phosphorylation of insulin receptor substrate-1 (IRS-1) by kinases like JNK disrupts the pathway, exacerbating hyperglycemia and beta-cell dysfunction. Dysregulation of the JAK-STAT pathway also plays a central role in autoimmune disorders, leading to excessive immune activation and inflammation. In conditions such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease, gain-of-function mutations or polymorphisms in JAK or STAT genes result in hyperactive signaling, promoting cytokine-driven inflammation and tissue damage. Targeted therapies, including Janus kinase (JAK) inhibitors like tofacitinib and baricitinib, have revolutionized treatment by selectively blocking these pathways, reducing disease activity and achieving remission in many patients as of 2025.^[77] Beyond oncology and endocrinology, aberrant signal transduction plays an emerging role in neurodegeneration. In Alzheimer's disease, amyloid-beta oligomers disrupt synaptic signaling by interfering with NMDA receptor function and calcium homeostasis, leading to impaired long-term potentiation and neuronal silencing. This synaptic decoupling contributes to cognitive decline through chronic disruption of neurotrophic pathways like BDNF/TrkB signaling. In infectious diseases, viruses exploit host signal transduction to promote replication and evade immunity. For instance, many viruses hijack the PI3K/AKT pathway to inhibit apoptosis and enhance viral protein synthesis, as seen in infections by human cytomegalovirus and influenza, thereby facilitating pathogenesis and chronic inflammation.

Historical Development

Foundational discoveries

The isolation of insulin in the early 1920s marked a pivotal empirical milestone in understanding hormonal signaling, demonstrating that specific molecules could regulate physiological processes like glucose metabolism. In 1921, Frederick G. Banting and Charles H. Best, working at the University of Toronto, extracted insulin from canine pancreases and successfully treated diabetic symptoms in dogs, leading to the first human applications by 1922.^[78] This discovery, awarded the 1923 Nobel Prize in Physiology or Medicine to Banting and J.J.R. Macleod, shifted early endocrinology from vague observations of glandular effects to targeted identification of signaling agents, though the intracellular mechanisms remained unknown.^[78] Prior to the 1950s, research on signal transduction was largely empirical, focusing on hormone isolation and phenotypic responses without molecular insight, as exemplified by studies on adrenaline and secretin in the 1920s–1940s. The field advanced dramatically in the 1950s–1960s with Earl W. Sutherland Jr.'s elucidation of cyclic adenosine monophosphate (cAMP) as an intracellular mediator. Beginning in the early 1950s, Sutherland's group at Vanderbilt University investigated epinephrine's activation of glycogenolysis in liver cells, identifying a heat-stable factor—later confirmed as cAMP in 1957 by T.W. Rall and colleagues—that amplified the hormone's signal without direct enzyme interaction.^[79] This introduced the "second messenger" concept, where extracellular signals like hormones trigger intracellular cascades via diffusible molecules, earning Sutherland the 1971 Nobel Prize in Physiology or Medicine.^[79] The idea revolutionized thinking, explaining how low hormone concentrations could elicit robust cellular responses through amplification steps. By the 1970s, investigations transitioned to molecular models, identifying guanine nucleotide-binding proteins (G proteins) as key transducers in signaling cascades. Martin Rodbell's work in the late 1960s at the National Institutes of Health revealed that glucagon's effects on liver membranes required GTP and a membrane-bound "transducer" to activate adenylate cyclase, the enzyme producing cAMP.^[80] Concurrently, Alfred G. Gilman at the University of Virginia, inspired by Rodbell's findings, purified and characterized these G proteins in the mid-1970s using toxin-perturbed S49 lymphoma cells, demonstrating their role in coupling receptors to effectors like adenylate cyclase.^[80] This built on the second messenger paradigm by outlining multi-component cascades—receptor, G protein, effector—enabling diverse signaling outcomes, and culminated in the 1994 Nobel Prize in Physiology or Medicine for Rodbell and Gilman. Post-1970s, these foundations facilitated a molecular era, contrasting pre-1950s descriptive approaches with detailed pathway dissections.^[8]

Recent advances

In the post-genomic era, research on signal transduction has transitioned from linear pathway models to integrated network perspectives, emphasizing interconnected dynamics and context-dependent regulation. This shift enables comprehensive analysis of how signals propagate through multifaceted interactions, as demonstrated by computational approaches like Petri net modeling, which use system invariants to predict network behaviors without kinetic parameters and reveal regulatory mechanisms in pathways such as TNFR1-NF-κB.^[81] Such methods highlight the limitations of isolated cascades and underscore the need for holistic views to address complexities in cellular decision-making. Systems biology tools, particularly phosphoproteomics, have driven this evolution by enabling high-throughput mapping of phosphorylation-based signaling events. For instance, SignalingProfiler 2.0 integrates transcriptomics, proteomics, and phosphoproteomics with prior knowledge networks from databases like SIGNOR to infer protein activities, reconstruct causal signaling architectures, and connect them to phenotypic hallmarks, as validated in EGF-stimulated HeLa cells and metformin-treated breast cancer models.^[82] Complementing this, optogenetics provides precise manipulation of pathways at subcellular resolutions, using light-inducible modules like CRY2-based systems to control protein-protein interactions and endogenous kinase activities, thereby dissecting temporal aspects of signaling in real-time.^[83] Meanwhile, single-cell profiling techniques, including mass cytometry and imaging mass cytometry, capture heterogeneous signaling dynamics by quantifying dozens of phosphorylation sites across thousands of cells, revealing variability in responses to stimuli that informs network heterogeneity in development and disease.^[84] Genome-wide CRISPR screens since the 2010s have systematically identified novel pathway components, such as negative regulators like UBASH3A in NF-κB signaling and FAM49B in actin dynamics within T cell receptor pathways, using methods like SLICE to perturb primary human T cells and uncover enhancers of proliferation and cytotoxicity.^[85]^[86] Building on this, 2020s advancements in AI modeling leverage machine learning to simulate network interactions from omics data, predicting drug-receptor bindings and pathway perturbations to accelerate targeted therapy design.^[87] Spatial aspects of signaling have also gained prominence through discoveries of liquid-liquid phase separation, where condensates of molecules like LAT and Grb2 form upon TCR activation to concentrate kinases such as ZAP70 while excluding phosphatases like CD45, thereby amplifying downstream ERK and actin responses.^[88] Additionally, the host microbiome modulates transduction networks via metabolites; for example, short-chain fatty acids activate G-protein-coupled receptors to regulate cAMP and NF-κB pathways, influencing immune and metabolic homeostasis, while lipopolysaccharide triggers TLR4-MyD88 signaling to promote inflammation in diseases like atherosclerosis.^[89] These developments reveal persistent knowledge gaps, including incomplete maps of microbial-host crosstalk and dynamic spatial organization, guiding future integrative studies.

References

[1]
Pathways of Intracellular Signal Transduction - The Cell - NCBI - NIH
In most cases, a chain of reactions transmits signals from the cell surface to a variety of intracellular targets—a process called intracellular signal ...
[2]
Cell–cell communication: new insights and clinical implications
Aug 7, 2024 · When cells communicate with each other, extracellular signals typically induce intracellular signal transduction cascades, leading to cellular ...
[3]
Signal Transduction as an Assimilation of Signals with Different ...
Jun 13, 2023 · Four original works and one review article focus on the molecules or mechanisms involved in the transduction of signals. Although signals ...
[4]
[PDF] cell signaling - UC Berkeley MCB
These molecules recognize and bind to receptors on the surface of target cells where they cause a cellular response by means of a signal transduction pathway.
[5]
Cell signalling: View as single page | OpenLearn
This relay of information along molecular pathways is called signal transduction; it is sometimes also simply referred to as 'signalling'.
[6]
Deciphering cell–cell interactions and communication from gene ...
Nov 9, 2020 · Given the promiscuity of receptors, physical compartmentalization of cells is key to limit ligand signalling and confer specificity to stem ...
[7]
A nexus for cellular homeostasis: the interplay between metabolic ...
The coordination of signal transduction and metabolic pathways is essential in maintaining a healthy and rapidly responsive cellular state.
[8]
Conceptual Evolution of Cell Signaling - PMC - PubMed Central - NIH
Signals are perturbations of cellular homeostasis and cells mainly respond to mechanical (mechanotransduction), electrical (electrotransduction), or chemical ( ...
[9]
Signalling change: signal transduction through the decades - Nature
May 2, 2013 · A growing understanding of the signal transduction processes sheds light on the mechanisms underlying drug resistance, particularly in cancer.Missing: biological review
[10]
Signal Transduction Pathway - an overview | ScienceDirect Topics
Signal transduction pathways are defined as processes that convey messages from ligands to induce changes in biological activity within target cells. These ...
[11]
Signaling Molecules and Their Receptors - The Cell - NCBI Bookshelf
The steroid hormones diffuse across the plasma membrane and bind to nuclear receptors, which directly stimulate transcription of their target genes. The steroid ...
[12]
Summary - The Cell - NCBI Bookshelf - NIH
Cell-cell signaling is divided into three general categories (endocrine, paracrine, and autocrine signaling) based on the distance over which signals are ...
[13]
GPCRs in Autocrine and Paracrine Regulations - PMC
In this review, we will focus on our current, yet evolving understanding of the autocrine and paracrine signals regulated by GPCRs in various physiological ...
[14]
Regulation of TRP Channels by Osmomechanical Stress - NCBI
Osmotic Stress (Osmotic-Induced Cell Volume Changes). Alterations in the osmolarity of the media surrounding the cell will lead to changes in cell volume as ...<|control11|><|separator|>
[15]
Structural features and mechanisms for sensing high osmolarity in ...
Osmolarity is a physico-chemical parameter that causes pleiotropic alterations in cell physiology. Recent research has revealed various mechanisms to sense high ...
[16]
Sensory transduction, the gateway to perception: mechanisms ... - NIH
Sensory transduction is the gateway to perception, where specialized cells sense stimuli like photons, molecules, and mechanical deflections. TRP channels are ...Missing: osmolarity | Show results with:osmolarity
[17]
Cellular mechanotransduction in health and diseases - Nature
Jul 31, 2023 · This review systematically summarizes the characteristics and regulatory mechanisms of typical mechanical cues in normal conditions and diseases with the ...
[18]
Physiological and Pathological Functions of Mechanosensitive Ion ...
Rapid sensation of mechanical stimuli is often mediated by mechanosensitve ion channels. Their opening results from conformational changes induced by mechanical ...
[19]
Role of Integrins in Endothelial Mechanosensing of Shear Stress
Through such mechanotransduction mechanisms, laminar shear stress upregulates genes involved in antiapoptosis, cell cycle arrest, morphological remodeling, and ...
[20]
Signal Transduction Pathways Leading to Heat Shock Transcription
The heat shock response (HSR) is a cellular mechanism for responding to a range of stresses, epitomized by heat shock, that result in protein inactivation.
[21]
Phototransduction Motifs and Variations - PMC - PubMed Central - NIH
In this Review, we have surveyed the phototransduction mechanisms in a range of ciliary and rhabdomeric photoreceptors from both vertebrates and invertebrates.
[22]
Phototransduction - Neuroscience - NCBI Bookshelf - NIH
Light activation causes a graded change in membrane potential and a corresponding change in the rate of transmitter release onto postsynaptic neurons.
[23]
Osmosensing and signaling in the regulation of mammalian cell ...
Oct 18, 2007 · This minireview summarizes recent progress in the understanding of how osmosensing and osmosignaling integrate into the overall context of growth factor ...Missing: osmolarity | Show results with:osmolarity
[24]
An Osmosensing Signal Transduction Pathway in Mammalian Cells
These data indicate that related protein kinases may mediate osmosensing signal transduction in yeast and mammalian cells.
[25]
A TRPV2–PKA Signaling Module for Transduction of Physical ...
Jul 12, 2004 · Cutaneous mast cell responses to physical (thermal, mechanical, or osmotic) stimuli underlie the pathology of physical urticarias.
[26]
Physiology, Cellular Receptors - StatPearls - NCBI Bookshelf - NIH
Sep 19, 2024 · The 3 types of cell-surface receptors include G protein–coupled receptors (GPCRs), ion channel receptors, and enzyme-linked receptors.Introduction · Cellular Level · Development · Pathophysiology
[27]
Biochemistry, G Protein Coupled Receptors - StatPearls - NCBI - NIH
The human genome encodes nearly 800 GPCRs, representing over 3% of human genes. ... many human diseases. For example, mutation of vasopressin V2 receptor ...
[28]
G protein-coupled receptors - C
About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (~400), taste (33), light perception (10) and ...
[29]
Cell Surface Receptors and Their Signal Transduction Pathways
The widely used RTK signal transduction pathway. The receptor tyrosine kinase is dimerized by the ligand, which causes the autophosphorylation of the receptor.The RTK pathway · The Smad pathway · The JAK-STAT pathway
[30]
https://www.sciencedirect.com/science/article/pii/B9780128035818102061
[31]
https://www.cell.com/cell/fulltext/S0092-8674(20)30218-X
[32]
Second Messengers - PMC - NIH
Abstract. Second messengers are small molecules and ions that relay signals received by cell-surface receptors to effector proteins.
[33]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4968160/
[34]
Phosphoinositide-specific phospholipase C in health and disease
DAG remains bound to the plasma membrane, whereas IP3 is located within the cytosol, but both of them can act as second messengers and activate downstream ...
[35]
The Cyclic AMP Pathway - PMC - NIH
cAMP was the first second messenger to be identified. Its three main effectors are PKA (which phosphorylates numerous metabolic enzymes), EPAC (a guanine ...Missing: review | Show results with:review
[36]
Compartmentalisation of second messenger signalling pathways
Compartmentalisation is a common mechanism used by all cells to ensure the interaction of signalling 'second messenger' molecules with localised 'pools' of ...
[37]
The crucial role of protein phosphorylation in cell signaling and its ...
In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and ...
[38]
MAP kinase pathways: The first twenty years - PMC - PubMed Central
The MAP kinases, discovered approximately twenty years ago, together with their immediate upstream regulators, are among the most highly studied signal ...Missing: original | Show results with:original
[39]
Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt ...
Jan 19, 2012 · In the present paper, we describe multiple levels of cross-talk between the PI3K (phosphoinositide 3-kinase)/Akt and Ras/MAPK (mitogen-activated protein kinase ...Missing: seminal | Show results with:seminal
[40]
Key signal transduction pathways and crosstalk in cancer
We outline the current general aspects of three key signaling pathways, including the MAPK pathway, PI3K/AKT/mTOR signaling, and Wnt/β-catenin signaling ...Missing: seminal | Show results with:seminal
[41]
Anchoring Proteins as Regulators of Signaling Pathways
Aug 3, 2012 · A-kinase anchoring proteins form the core of multiprotein complexes and enable simultaneous but segregated cAMP signaling events to occur in defined cellular ...
[42]
Bigger, better, faster: principles and models of AKAP signaling - NIH
Here we review computational models that have incorporated AKAPs into signaling networks as well as several models of other relevant protein scaffolds. The ...
[43]
Context-dependent transcriptional regulations between signal ...
Jan 13, 2011 · Cells coordinate their metabolism, proliferation, and cellular communication according to environmental cues through signal transduction.
[44]
CELL SIGNALLING DYNAMICS IN TIME AND SPACE - PMC
The specificity of cellular responses to receptor stimulation is encoded by the spatial and temporal dynamics of downstream signalling networks.
[45]
Ligand-Gated Ion Channels - Neuroscience - NCBI Bookshelf - NIH
Ligand-Gated Ion Channels ... Many types of ion channels respond to chemical signals (ligands) rather than to changes in the membrane potential (Figure 4.4E-G).
[46]
Ligand-Gated Ion Channels - PMC - PubMed Central
Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma ...Missing: transduction | Show results with:transduction
[47]
Signal Transduction and the Cytoskeleton - The Cell - NCBI Bookshelf
Components of the cytoskeleton thus act as both receptors and targets in cell signaling pathways, integrating cell shape and movement with other cellular ...
[48]
The Roles of Signaling in Cytoskeletal Changes, Random ...
In this review we discuss recent advances in our understanding of signal transduction networks related to direction-sensing and movement.
[49]
Biochemistry, cAMP - StatPearls - NCBI Bookshelf - NIH
The production of cAMP is regulated by Adenylyl Cyclase and phosphodiesterase. · Once the signaling has occurred, cAMP is hydrolyzed to 5'-AMP.
[50]
Signaling in Muscle Contraction - PMC - PubMed Central - NIH
In all muscle cells, contraction depends on a rise in cytosolic calcium. Signaling pathways control the release of calcium from intracellular stores, as well as ...
[51]
Unraveling the mechanisms of calcium-dependent secretion - PMC
Ca2+-dependent secretion is a process by which important signaling molecules that are produced within a cell—including proteins and neurotransmitters—are ...Missing: transduction | Show results with:transduction
[52]
G protein-coupled receptors (GPCRs): advances in structures ...
Apr 10, 2024 · GPCRs are the largest superfamily of cell surface membrane receptors and are encoded by approximately 1000 genes, sharing conserved seven-transmembrane (7TM) ...
[53]
How activated receptors couple to G proteins - PNAS
Activated receptors (R*) can then activate heterotrimeric G proteins (composed of α.GDP, β, and γ subunits) on the inner surface of the cell membrane.
[54]
G Protein-Coupled Receptors as Targets for Approved Drugs - NIH
We estimate that ∼700 approved drugs target GPCRs, implying that approximately 35% of approved drugs target GPCRs.
[55]
Receptor tyrosine kinases: mechanisms of activation and signaling
RTKs are activated by ligand binding, typically dimerization, leading to autophosphorylation. This activates the receptor and allows downstream signaling.
[56]
Mechanisms of receptor tyrosine kinase activation in cancer
Feb 19, 2018 · In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms ...
[57]
EGFR and Lung Cancer | American Lung Association
Jul 18, 2025 · EGFR-positive lung cancer represents about 10-15% of lung cancers in the United States and most often appears in the adenocarcinoma subtype of non-small cell ...<|separator|>
[58]
Ultrafast structural changes direct the first molecular events of vision
Mar 22, 2023 · Rhodopsin transforms the absorption of light into a physiological signal through conformational changes that activate the intracellular G ...Missing: sensory | Show results with:sensory
[59]
Insulin signaling in health and disease - JCI
Jan 4, 2021 · The rate-limiting step in insulin's control of glucose homeostasis is stimulation of glucose transport in fat and muscle (99, 123, 124). This ...
[60]
Wnt/β-catenin signalling: function, biological mechanisms ... - Nature
Jan 3, 2022 · Wnt/β-catenin signal transduction is an important regulator of embryonic development and adult homeostasis and is also closely related to ...
[61]
Wnt signaling in development and tissue homeostasis
Jun 8, 2018 · The Wnt-β-catenin signaling pathway is one of the evolutionary conserved communication systems that regulates embryonic development. It ...Wnt signal amplification · Wnt signaling in early... · Wnt signaling in embryonic...
[62]
Signal Transduction in Immune Cells and Protein Kinases - PubMed
Protein kinases involvement in innate immune cells are presented within the chapter emphasizing their coordination in many aspects of immune cell function.
[63]
Examples of Neuronal Signal Transduction - Neuroscience - NCBI
Three important signal transduction pathways can illustrate some of the roles of intracellular signal transduction processes in the nervous system.
[64]
Gonadotropin Cell Transduction Mechanisms - PMC - PubMed Central
Jun 4, 2022 · The orchestrated signaling activation promotes different biological responses, such as ovarian angiogenesis, folliculogenesis, oocyte selection, ...
[65]
Notch signaling pathway: architecture, disease, and therapeutics
Mar 24, 2022 · NOTCH signaling is involved in multiple aspects of metazoans' life, including cell fate decisions, embryo and tissue development, tissue ...
[66]
Evolution of protein kinase signaling from yeast to man - PubMed
To explore the evolution of protein phosphorylation, we compared the protein kinase complements ('kinomes') of budding yeast, worm and fly, with known human ...
[67]
The Nobel Prize in Physiology or Medicine 1923 - NobelPrize.org
The Nobel Prize in Physiology or Medicine 1923 was awarded jointly to Frederick Grant Banting and John James Rickard Macleod for the discovery of insulin.
[68]
The Nobel Prize in Physiology or Medicine 1971 - NobelPrize.org
The Nobel Prize in Physiology or Medicine 1971 was awarded to Earl W. Sutherland, Jr. for his discoveries concerning the mechanisms of the action of hormones.Missing: cAMP 1950s
[69]
The Nobel Prize in Physiology or Medicine 1994 - NobelPrize.org
The Nobel Prize in Physiology or Medicine 1994 was awarded jointly to Alfred G. Gilman and Martin Rodbell for their discovery of G-proteins.
[70]
Computational modeling of signal transduction networks without ...
Signal transduction pathways are often highly intertwined, and sensitive regulation is essential for the understanding of biological and physiological functions ...
[71]
SignalingProfiler 2.0 a network-based approach to bridge multi ...
Aug 23, 2024 · SignalingProfiler 2.0 derives context-specific signaling networks by integrating proteogenomic data with the prior knowledge-causal network.
[72]
Optogenetics: The Art of Illuminating Complex Signaling Pathways
Optogenetic methods enable manipulation of signaling processes with precise timing and local control. In this review, we describe recent optogenetic approaches ...
[73]
https://pmc.ncbi.nlm.nih.gov/articles/PMC9181808/
[74]
https://www.nature.com/articles/s41392-022-00934-y
[75]
Molecular mechanisms of signaling transduction pathways of drug ...
May 22, 2025 · This comprehensive review delves into the molecular mechanisms of signaling transduction pathways associated with pharmacological target molecules.
[76]
Phase separation of signaling molecules promotes T cell receptor ...
These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.
[77]
Microbiota in health and diseases | Signal Transduction ... - Nature
Apr 23, 2022 · Microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases (CVDs), cancers, respiratory diseases, etc.