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Extracellular signal-regulated kinases

Extracellular signal-regulated kinases (ERKs), also known as classical MAP kinases, are a subfamily of ubiquitous serine/threonine protein kinases that transduce extracellular signals—such as growth factors, mitogens, and stresses—into diverse intracellular responses, primarily regulating cell proliferation, differentiation, survival, and gene expression.^[1] The two primary isoforms, ERK1 (also called p44 MAPK, encoded by MAPK3 on chromosome 16) and ERK2 (p42 MAPK, encoded by MAPK1 on chromosome 22), share approximately 84% amino acid sequence identity and are evolutionarily conserved across eukaryotes, with ERK1 consisting of 379 residues and ERK2 of 360 residues.^[1] These kinases were first identified in 1987 as microtubule-associated protein 2 (MAP2) kinases and formally named ERKs in 1991 following the cloning of their genes in rats.^[1] ERKs belong to the broader mitogen-activated protein kinase (MAPK) superfamily, which also includes the c-Jun N-terminal kinases (JNKs), p38 MAPKs, and ERK5 (Big MAPK1), but ERKs are distinguished by their preferential activation by mitogenic stimuli via receptor tyrosine kinases (RTKs).^[2] Structurally, both ERK1 and ERK2 feature a conserved catalytic core with an N-terminal lobe (containing β-sheets and the αC-helix) and a C-terminal lobe (rich in α-helices), along with a kinase insert domain of 31 residues that contributes to substrate specificity; they lack a classical nuclear localization signal but can translocate to the nucleus upon activation.^[1] Activation occurs through a canonical three-tiered kinase cascade: extracellular ligands bind RTKs, leading to recruitment of the guanine nucleotide exchange factor Sos via the adaptor protein Grb2, which activates Ras GTPase; Ras then recruits and activates Raf kinases (ARAF, BRAF, or CRAF), which in turn phosphorylate and activate MAPK/ERK kinases (MEK1/2) on serine residues; finally, MEK1/2 dually phosphorylate ERKs on a conserved Thr-X-Tyr motif (Thr183/Tyr185 in ERK2; Thr202/Tyr204 in ERK1), inducing a conformational change that enables substrate binding.^[2] This phosphorylation is essential for full catalytic activity, with docking sites (D-site on substrates and F-site on ERKs) enhancing specificity for over 175 known substrates, including transcription factors like Elk-1 and c-Fos, ribosomal S6 kinases (RSKs), and cytoskeletal proteins like palladin.^[1] In physiological contexts, ERKs orchestrate critical cellular processes, including cell cycle progression (e.g., via cyclin D1 induction), migration and adhesion (through myosin light chain kinase phosphorylation), synaptic plasticity and memory formation in neurons, embryonic development (such as trophoblast differentiation), and metabolic regulation.^[2] For instance, ERK signaling is indispensable for proper brain development and repair,^[2] as well as vascular smooth muscle cell growth and vasoconstriction.^[3] Dysregulation of the ERK pathway, often due to upstream mutations in Ras (present in ~30% of human cancers) or BRAF (e.g., V600E mutation in 40–60% of melanomas), leads to sustained activation and promotes oncogenesis, metastasis, drug resistance, and inflammation-associated diseases like Alzheimer's and cardiac ischemia-reperfusion injury.^[1] Therapeutically, ERK inhibitors (e.g., ATP-competitive agents like FR180204) and upstream blockers (e.g., BRAF inhibitor vemurafenib, FDA-approved for BRAF-mutant melanoma) have shown promise in targeting these hyperactive pathways, though challenges like paradoxical activation and resistance remain.^[1] As of 2025, several direct ERK1/2 inhibitors are under investigation in clinical trials for various cancers and other conditions.^[4]

Introduction

Definition and Classification

Extracellular signal-regulated kinases (ERKs) are serine/threonine-specific protein kinases that belong to the mitogen-activated protein kinase (MAPK) superfamily, which transduces extracellular signals into intracellular responses.^[5] These kinases are primarily activated by mitogens, growth factors, and other extracellular stimuli, such as cytokines, that bind to cell surface receptors, initiating a signaling cascade that ultimately regulates cellular processes like proliferation and differentiation.^[6] As key effectors in this pathway, ERKs phosphorylate downstream targets to modulate gene expression and cytoskeletal dynamics, thereby linking environmental cues to nuclear events.^[5] ERKs are classified into conventional and atypical variants based on their structural features, activation mechanisms, and sequence homology. The conventional ERKs, primarily ERK1 (also known as MAPK3) and ERK2 (MAPK1), share high sequence similarity and are the most studied isoforms, functioning as prototypical members of the family.^[6] In contrast, atypical ERKs, including ERK3/4 and ERK7/8, exhibit divergent activation loops and regulatory domains, leading to distinct phosphorylation patterns and independence from classical MAPK kinase (MAPKK) activation in some cases.^[5] This classification underscores their roles in signal transduction from plasma membrane receptors to the nucleus, where they influence transcription factors and promote cell survival and growth.^[6] Within the broader MAPK superfamily, ERKs form one of the major modules alongside the c-Jun N-terminal kinase (JNK) and p38 pathways, each responding to specific stimuli. While JNK and p38 modules are predominantly activated by environmental stresses, such as UV radiation or osmotic shock, leading to responses like apoptosis and inflammation, the ERK module is specialized for mitogenic signals that drive cell proliferation and survival.^[5] This modular organization allows for precise signal specificity, with ERKs serving as the terminal kinases in the canonical RAS-RAF-MEK-ERK cascade, where sequential phosphorylation by upstream activators integrates growth-promoting inputs.^[6]

Discovery and Historical Context

The discovery of extracellular signal-regulated kinases (ERKs) emerged from studies on signal transduction in the late 1980s, building on the broader identification of mitogen-activated protein kinases (MAPKs) during that decade. Initial observations identified a 42-kDa protein kinase, termed pp42 or MAP kinase, that was rapidly phosphorylated and activated in response to growth factors such as insulin and nerve growth factor (NGF). This kinase was first characterized in mammalian cells, including 3T3-L1 adipocytes, where it phosphorylated microtubule-associated protein 2 (MAP-2) following insulin stimulation. In parallel, research on Xenopus laevis oocytes revealed pp42 and a related pp44 isoform activated by progesterone, linking the kinase to meiotic maturation processes. These findings established ERKs as key responders to extracellular mitogenic signals, initially dubbed "MAP-2 kinases" due to their substrate specificity. Cloning efforts in the early 1990s solidified the molecular identity of ERKs. In 1990, Thomas G. Boulton and colleagues cloned the cDNA for ERK1 (MAPK3), a 44-kDa serine/threonine kinase from rat PC12 cells, demonstrating its activation and tyrosine phosphorylation in response to insulin and NGF. Shortly thereafter, ERK2 (MAPK1), a 42-kDa isoform sharing approximately 85% sequence identity with ERK1, was cloned from rat brain and shown to exhibit similar mitogen-responsive properties. A pivotal milestone came in 1992 with the identification of mitogen-activated protein kinase kinase (MEK), the dual-specificity upstream activator that phosphorylates both threonine and tyrosine residues on ERKs, enabling their full activation. Throughout the 1990s, ERKs were linked to the RAS signaling pathway, particularly in oncogenesis, as oncogenic RAS mutations were found to constitutively activate the RAF-MEK-ERK cascade, promoting uncontrolled cell proliferation in various cancers. The nomenclature evolved to reflect these insights, shifting from "MAP-2 kinases" to "extracellular signal-regulated kinases" (ERKs) in seminal 1991 publications, emphasizing their role in transducing extracellular cues rather than solely their substrate affinity. This reclassification highlighted ERKs' position within the MAPK superfamily and their integration into multi-tiered kinase cascades. In the post-genomics era, particularly from the 2010s to 2025, ERKs have been incorporated into systems biology models to dissect dynamic signaling networks, such as through computational simulations of ERK oscillations and feedback loops in response to stimuli like epidermal growth factor. These models, informed by high-throughput phosphoproteomics, have elucidated ERK's context-dependent roles in cellular decision-making, aiding predictions of pathway dysregulation in diseases. Recent advances as of 2025 include the development of selective ERK1/2 inhibitors for cancer therapy and insights into ERK signaling in myelination and mechanotransduction.^[4]^[7]

Structure and Isoforms

Core Structural Features

Extracellular signal-regulated kinases (ERKs) exhibit a conserved domain architecture typical of eukaryotic protein kinases, consisting of an N-terminal regulatory domain, a central bilobal kinase domain, and C-terminal docking sites. The N-terminal domain, approximately 30-40 residues long, contributes to regulatory interactions and stability, while the kinase domain spans about 300 residues and folds into a small N-lobe (primarily β-strands and the αC-helix) and a larger C-lobe (dominated by α-helices), with the ATP-binding cleft located at the interface connected by a flexible hinge region.^[8] The C-terminal extension, around 40-50 residues, houses docking motifs essential for substrate and scaffold interactions.^[9] Central to ERK function is the activation loop (A-loop) within the kinase domain, featuring the conserved TEY motif (Thr-Glu-Tyr, specifically Thr183-Glu184-Tyr185 in human ERK2), which undergoes dual phosphorylation to induce catalytic activation. This motif is positioned between the N- and C-lobes, and in its unphosphorylated state, it obstructs the active site; phosphorylation repositions it to stabilize the catalytic conformation. Additionally, ERKs contain D-motif (docking domain, characterized by a basic patch followed by hydrophobic L/I-X-L/I residues) and F-motif (FXFP, where X is any residue and F is phenylalanine) sites in the C-terminal region and kinase domain, respectively, which facilitate specific binding to upstream activators, substrates, and phosphatases.^[10] Structurally, ERKs share key features with other mitogen-activated protein kinases (MAPKs), including a conserved glycine-rich loop (G-loop, sequence GXGXXG) in the N-lobe that coordinates the phosphate groups of ATP and a set of catalytic spine residues (such as Asp in the HRD motif of the catalytic loop) that align upon activation to form the active site. These elements ensure precise nucleotide binding and phosphotransfer, with the G-loop interacting directly with the β- and γ-phosphates of ATP.^[8]^[11] Activation triggers significant conformational changes in ERKs, transitioning from an inactive, unphosphorylated state where the αC-helix is displaced and the A-loop is disordered to an active, doubly phosphorylated state with the αC-helix docked and the A-loop extended to expose the substrate-binding site. The hinge region exhibits flexibility, enabling lobe movements that accommodate substrate access, as observed in comparisons between unphosphorylated and phosphorylated structures.^[12]^[11] This structural framework is evolutionarily conserved across species, from yeast homologs like Fus3 to mammalian ERKs, reflecting ancient origins in the MAPK superfamily; the human ERK2 crystal structure (PDB: 2ERK) exemplifies this conservation, showing near-identical folding with orthologs in distant taxa.^[13]^[14]

Specific Isoforms: ERK1 and ERK2

Extracellular signal-regulated kinase 1 (ERK1), also known as MAPK3 or p44MAPK, is encoded by the MAPK3 gene located on human chromosome 16p11.2.^[15] The protein consists of 379 amino acids and exhibits higher expression levels in tissues such as the brain and heart compared to other isoforms.^[16] ERK1 shares approximately 84% amino acid sequence identity with ERK2 and displays subtle differences in substrate affinity, potentially influencing its regulatory roles in downstream signaling.^[17] ERK2, or MAPK1 (p42MAPK), is encoded by the MAPK1 gene on chromosome 22q11.22 and comprises 360 amino acids.^[18] Unlike ERK1, ERK2 demonstrates ubiquitous expression across various tissues and cell types.^[19] This isoform plays a central role in mitogenic responses due to its broad distribution and high conservation.^[19] Genetic studies reveal both redundancy and non-redundancy between ERK1 and ERK2. Knockout of ERK1 results in viable mice with mild proliferative defects, while ERK2 knockout leads to embryonic lethality around implantation, underscoring ERK2's essential role in early development.^[19] However, combined inactivation demonstrates functional compensation, where ERK1 partially substitutes for ERK2 in proliferation and placental development, with overall ERK activity levels determining phenotypic severity.^[20] Double knockouts are embryonic lethal, confirming their overlapping yet critical contributions.^[21] Tissue-specific roles further highlight their distinctions: ERK2 predominates in embryonic development and early proliferative events, as evidenced by its necessity for post-implantation viability.^[19] In contrast, ERK1 supports adult cell proliferation, potentially by modulating ERK2 activity to fine-tune Ras-dependent growth responses.^[22] Post-translational modifications contribute to their unique functions, including a nuclear export signal associated with ERK2 that facilitates its cytoplasmic retention via interaction with MEK1's export machinery.^[23] This mechanism, distinct from ERK1's slower nucleocytoplasmic shuttling due to N-terminal extensions, enables regulated localization and signaling specificity.^[24]

ERK5 and Atypical ERKs

ERK5, also known as mitogen-activated protein kinase 7 (MAPK7) or big MAPK1 (BMK1), is the largest member of the ERK family, comprising 816 amino acids and featuring a distinctive C-terminal extension beyond the conserved kinase domain.^[25] This extension includes a nuclear localization signal and a transcriptional activation domain that enables ERK5 to directly regulate gene expression upon translocation to the nucleus.^[26] Unlike the canonical ERK1 and ERK2, which exhibit functional redundancy in many contexts, ERK5's unique structural elements confer specialized roles in cellular signaling. ERK5 is activated through dual phosphorylation on threonine 219 and tyrosine 221 within its TEY motif by its specific upstream kinase, MEK5 (MAP2K5), followed by autophosphorylation of the C-terminal tail that relieves auto-inhibition and promotes nuclear import.^[27] The C-terminal tail acts as an auto-inhibitory element in the inactive state, docking over the kinase domain to block substrate access, a feature not present in ERK1/2.^[28] The MAPK7 gene, located on human chromosome 17p11.2, spans approximately 5.8 kb and consists of nine exons.^[29] ERK5 plays a critical role in cardiovascular development, particularly in angiogenesis and cardiac morphogenesis, as evidenced by studies in mouse models.^[30] Homozygous knockout of Erk5 in mice results in embryonic lethality between days 9.5 and 10.5, characterized by severe defects in vascular remodeling, including impaired extraembryonic vasculature and failure of blood vessel formation in the yolk sac and embryo proper.^[31] These phenotypes highlight ERK5's non-redundant function in early embryonic vascular development, distinct from the milder disruptions seen in ERK1/2 knockouts.^[32] Atypical ERKs, including ERK3 (MAPK6) and ERK4 (MAPK4), diverge significantly from classical ERKs like ERK1/2 and ERK5 in structure and activation mechanisms.^[33] Both lack the conserved TEY dual phosphorylation motif in their activation loop, instead featuring a single serine-glutamate-glycine (SEG) motif—Ser189 in ERK3 and the equivalent (Ser186) in ERK4—that undergoes constitutive phosphorylation, rendering ERK3 approximately 100% phosphorylated on this residue in vivo.^[34] This absence of the typical activation loop structure leads to reliance on alternative activation pathways, such as interaction with and phosphorylation by MAPK-activated protein kinase 5 (MK5/PRAK), rather than dual-specificity MEK kinases; for instance, ERK3 binds MK5 to facilitate its cytoplasmic retention and activation of downstream targets.^[35] ERK4 shares similar atypical features, with major sequence differences confined to its C-terminal region, and both kinases exhibit prolonged stability and atypical subcellular localization compared to classical ERKs.^[36] Recent research as of 2025 has expanded understanding of ERK5's roles beyond developmental processes, particularly in inflammation. ERK5 modulates proinflammatory cytokine release from monocytes and endothelial cells, promoting neutrophil adhesion and contributing to vascular inflammation in conditions like atherosclerosis.^[37] In endothelial cells, ERK5 activation via upstream kinases like TNIK suppresses adhesion molecule expression while upregulating anti-inflammatory factors such as endothelial nitric oxide synthase (eNOS), suggesting context-dependent pro- and anti-inflammatory effects that warrant careful consideration in therapeutic targeting.^[38] Studies in osteoarthritis models further implicate ERK5 in sustaining inflammatory signaling within articular cartilage, linking it to chronic inflammatory diseases.^[39]

Activation and Signaling Pathway

Upstream Activation Cascade

The upstream activation cascade of extracellular signal-regulated kinases (ERKs) primarily occurs through the canonical mitogen-activated protein kinase (MAPK) pathway, which transduces extracellular signals from growth factors to intracellular responses. In this pathway, receptor tyrosine kinases (RTKs) such as the epidermal growth factor receptor (EGFR) are activated upon binding of ligands like epidermal growth factor (EGF). Ligand binding induces RTK dimerization and autophosphorylation on tyrosine residues, creating docking sites for adaptor proteins. The adaptor protein GRB2, bound to the guanine nucleotide exchange factor son of sevenless (SOS), is recruited to these phosphotyrosine sites via its SH2 domain, thereby localizing SOS to the plasma membrane. SOS then catalyzes the exchange of GDP for GTP on RAS proteins (HRAS, KRAS, NRAS), converting RAS to its active GTP-bound form.^[40]^[41] Active RAS-GTP recruits RAF kinases to the plasma membrane, initiating their activation. The RAF family includes three isoforms: ARAF, BRAF, and CRAF (also known as RAF1), each capable of interacting with RAS but differing in tissue expression and regulatory requirements; for instance, BRAF is highly expressed in neural tissues and is frequently mutated in cancers. RAS binding facilitates RAF translocation and subsequent activation steps, leading to RAF-mediated phosphorylation of mitogen-activated protein kinase kinases (MEK1 and MEK2) on serine/threonine residues. Scaffold proteins such as kinase suppressor of RAS 1 and 2 (KSR1 and KSR2) play a critical role in organizing the cascade by simultaneously binding RAF, MEK, and ERK, thereby enhancing signal specificity, efficiency, and preventing crosstalk with other pathways.^[40]^[42]^[43] Non-canonical inputs also converge on the RAS/RAF axis to activate the ERK cascade. G-protein-coupled receptors (GPCRs), upon agonist stimulation, can transactivate RTKs or directly engage RAS through beta-arrestin-mediated mechanisms, leading to RAF activation independent of growth factors. Integrins, adhesion receptors sensing extracellular matrix, activate RAS via focal adhesion kinase (FAK) and subsequent GRB2-SOS recruitment. Additionally, cellular stress signals, such as UV radiation or osmotic stress, can phosphorylate RAF through kinases like p21-activated kinase (PAK), bypassing RTK involvement. Crosstalk with the phosphoinositide 3-kinase (PI3K)/AKT pathway modulates this cascade, as active AKT phosphorylates and inhibits RAF isoforms, particularly CRAF, thereby attenuating ERK signaling under certain conditions. MEK1/2 serve as the direct upstream activators of ERK1/2 in all these pathways.^[40]^[44]^[45]

Phosphorylation and Dimerization

The activation of extracellular signal-regulated kinases (ERKs), particularly ERK1 and ERK2, culminates in dual phosphorylation by mitogen-activated protein kinase kinases (MEK1/2), which targets specific residues within the TEY motif of the activation loop. For ERK2, this involves phosphorylation at threonine 183 (Thr183) and tyrosine 185 (Tyr185), while for ERK1, the sites are threonine 202 (Thr202) and tyrosine 204 (Tyr204).^[46] This sequential phosphorylation—first on tyrosine by MEK, followed by threonine—induces a conformational rearrangement in the kinase domain, repositioning the activation loop to expose the catalytic cleft and enable substrate binding.^[47] The result is a dramatic increase in kinase activity, exceeding 1000-fold compared to the unphosphorylated state, allowing ERKs to efficiently phosphorylate downstream targets.^[46] Specificity in ERK signaling is further ensured through docking interactions mediated by the D-domain (also known as the δ-domain), a short linear motif present on substrates and upstream activators like MEK. This motif, typically characterized by a basic region followed by hydrophobic residues (e.g., R/K-X_{2-6}-L/I-X-L/I), binds to a complementary docking groove on the ERK surface, distinct from the active site, thereby facilitating precise recruitment and phosphorylation.^[48] Upon dual phosphorylation, the conformational shift in the TEY motif not only activates the catalytic site but also enhances affinity for these D-domains, promoting efficient signal propagation while minimizing off-target effects.^[49] Following phosphorylation, activated ERK1 and ERK2 undergo homo- or heterodimerization, a process critical for their translocation from the cytoplasm to the nucleus and amplification of signaling. Dimer formation occurs via interfaces involving the ATP-binding pocket and activation loop, stabilizing the active conformation and shielding phosphorylated residues from premature dephosphorylation.^[50] This dimerization is essential for nuclear import, as monomeric ERKs translocate inefficiently, and it enhances the duration and potency of ERK-mediated responses in the nucleus.^[51] Signal termination at the ERK level is achieved through rapid dephosphorylation by dual-specificity phosphatases (DUSPs) and protein phosphatase 2A (PP2A). DUSPs, such as DUSP1, DUSP4, and DUSP6, specifically target the phosphothreonine and phosphotyrosine residues in the TEY motif, inactivating ERK with high selectivity for the MAPK family.^[52] Meanwhile, PP2A holoenzymes containing B56 regulatory subunits directly dephosphorylate ERK without interfering with upstream MEK activity, providing a spatiotemporal control mechanism.^[53] These phosphatases ensure transient ERK activation, preventing sustained signaling that could lead to dysregulation. The kinetics of ERK phosphorylation and dimerization reflect the pathway's responsiveness, with activation occurring rapidly—often peaking within minutes of upstream stimuli from the RAS-RAF-MEK cascade—followed by feedback loops that attenuate the signal. Negative feedback, including ERK-mediated phosphorylation of upstream components like RAF and SOS, curtails activity within 10-30 minutes, while DUSP induction provides longer-term inactivation.^[54]^[55] This dynamic balance allows ERKs to process diverse inputs into precise temporal patterns of signaling.

Biological Functions

Regulation of Gene Expression

Upon activation through dual phosphorylation on the TEY motif, ERK1/2 translocate from the cytoplasm to the nucleus, a process facilitated by importin 7, enabling access to nuclear substrates.^[56] In the nucleus, activated ERKs phosphorylate transcription factors including Elk-1, c-Fos, and c-Myc, thereby enhancing their DNA-binding affinity and transcriptional activity.^[57] For instance, ERK-mediated phosphorylation of Elk-1 at multiple serine residues in its C-terminal domain potentiates its transactivation potential.^[58] A key mechanism of ERK-driven transcription involves the formation of ternary complexes at serum response elements (SREs) in promoters of immediate-early genes, such as c-fos. In this complex, ERK-phosphorylated Elk-1 (an ETS-domain ternary complex factor, TCF) interacts with serum response factor (SRF) to drive SRE-dependent gene induction.^[58] This phosphorylation-dependent ternary complex assembly is essential for mitogen-induced c-fos expression, as unphosphorylated Elk-1 forms weaker complexes with reduced transcriptional output.^[59] ERK signaling also establishes negative feedback loops by inducing the expression of dual-specificity phosphatase (DUSP) genes, such as DUSP6, which dephosphorylate and inactivate ERKs to attenuate the signal.^[60] This ERK-dependent transcription of DUSPs, often via Elk-1/SRE pathways, limits the duration of nuclear ERK activity and prevents excessive gene activation.^[61] Beyond direct TF phosphorylation, ERKs exert epigenetic control by activating mitogen- and stress-activated protein kinases (MSK1/2), which phosphorylate histone H3 at serine 10 and 28 to promote chromatin remodeling and immediate-early gene transcription.^[62] ERK phosphorylation of MSK1/2 in multiprotein complexes facilitates histone H3 modifications that displace repressive factors like HP1γ and recruit RNA polymerase II, enhancing promoter accessibility.^[63] Quantitative models of ERK signaling reveal that transcriptional outputs are dose-dependent on signal strength, duration, and frequency, with sustained or pulsed ERK activity differentially activating immediate-early versus late-response genes.^[64] For example, mathematical simulations show that higher ERK amplitudes increase transcription rates of target genes like c-fos, while prolonged activation sustains expression of downstream effectors, decoding signal intensity into specific gene programs.^[65]

Involvement in Cellular Processes

Extracellular signal-regulated kinases (ERKs) play a pivotal role in promoting cell proliferation by facilitating the G1/S phase transition through the regulation of key cell cycle proteins. Specifically, ERK activation induces the expression of cyclin D1, which forms a complex with cyclin-dependent kinase 4/6 (CDK4/6) to phosphorylate the retinoblastoma protein (Rb), thereby releasing E2F transcription factors that drive the progression into S phase.^[66] This process is essential for mitogenic responses in various cell types, including fibroblasts and epithelial cells.^[57] In addition to proliferation, ERKs contribute to cell differentiation and survival by modulating apoptotic pathways in the cytoplasm. ERK-mediated phosphorylation of the pro-apoptotic protein Bim at multiple sites promotes its ubiquitination and proteasomal degradation, thereby preventing mitochondrial outer membrane permeabilization and inhibiting apoptosis.^[67] Similarly, ERKs indirectly phosphorylate Bad at serine 112 via activation of p90 ribosomal S6 kinase (RSK), leading to its sequestration by 14-3-3 proteins and dissociation from anti-apoptotic Bcl-2 family members like Bcl-xL, which enhances cell survival during stress or growth factor stimulation.^[68] In neuronal contexts, sustained ERK signaling is required for the differentiation of embryonic stem cells into neurons, promoting neurite outgrowth and survival through phosphorylation of cytoplasmic targets that stabilize the cytoskeleton.^[69] ERKs also regulate cell migration and adhesion dynamics by targeting components of the focal adhesion complex and cytoskeleton. Phosphorylation of focal adhesion kinase (FAK) by ERK enhances its activation, facilitating the recruitment of paxillin and promoting focal adhesion turnover necessary for lamellipodia protrusion and directed motility.^[70] Furthermore, ERK phosphorylates myosin light chain kinase (MLCK), which increases actomyosin contractility at the rear of migrating cells, aiding in detachment from the extracellular matrix and overall cell movement.^[71] These actions are critical in processes such as wound healing and embryonic development. On the metabolic front, ERKs influence glucose homeostasis by phosphorylating glycogen synthase kinase 3β (GSK3β) at threonine 43, which primes it for subsequent inactivation and thereby supports glycogen synthesis and insulin-like signaling effects.^[72] This phosphorylation event links ERK to the modulation of metabolic enzymes, enhancing cellular responses to nutrient availability without directly overlapping with primary insulin receptor pathways. The functional outcomes of ERK signaling are highly context-dependent, particularly influenced by the duration of activation. Transient ERK activation typically drives proliferation by rapidly inducing cyclin D1 expression, whereas sustained activation promotes differentiation and survival through prolonged phosphorylation of targets like Bim and cytoskeletal regulators.^[73] This temporal distinction arises from feedback mechanisms, such as phosphatase activity and scaffold proteins, that shape signal duration in response to specific ligands like epidermal growth factor versus nerve growth factor.^[66]

Pathophysiological Roles

Role in Cancer

Extracellular signal-regulated kinases (ERKs) play a pivotal role in cancer through hyperactivation of the MAPK/ERK pathway, which drives oncogenesis by promoting uncontrolled cell growth and survival. Oncogenic mutations upstream of ERKs, such as in BRAF and RAS, lead to constitutive signaling that bypasses normal regulatory mechanisms, resulting in sustained ERK phosphorylation and downstream effects that favor tumor initiation and progression.^[74] A prominent example is the BRAF V600E mutation, present in approximately 50% of melanomas, which causes constitutive activation of the RAF-MEK-ERK cascade independent of upstream receptor tyrosine kinase input, thereby enhancing tumor cell proliferation and survival. Similarly, activating KRAS mutations occur in over 90% of pancreatic ductal adenocarcinomas, where they lock the pathway in an active state, leading to persistent ERK signaling that supports early malignant transformation and invasion.^[75]^[76] In tumor promotion, hyperactive ERK signaling enhances cellular proliferation by upregulating cyclins and inhibiting apoptosis regulators, while also inducing angiogenesis through phosphorylation of hypoxia-inducible factor 1α (HIF-1α), which transcriptionally activates vascular endothelial growth factor (VEGF) expression to support neovascularization. Furthermore, ERK promotes metastasis by inducing matrix metalloproteinase 9 (MMP9) expression, facilitating extracellular matrix degradation and tumor cell dissemination to distant sites.^[74]^[77]^[78] ERK pathway reactivation via feedback loops contributes to resistance against targeted therapies, particularly after epidermal growth factor receptor (EGFR) inhibitors, where relief of negative feedback on receptor tyrosine kinases restores ERK activity and sustains tumor growth in EGFR-mutant cancers. Recent studies as of 2025 have highlighted ERK-driven immune evasion as a mechanism of immunotherapy resistance; for instance, oncogenic KRAS signaling via the ERK/MAPK pathway upregulates PD-L1 expression in non-small cell lung cancer, leading to T-cell exhaustion and reduced efficacy of PD-1/PD-L1 blockade.^[79]^[80] Phosphorylated ERK (phospho-ERK) serves as a diagnostic and prognostic biomarker in colorectal cancer, with elevated nuclear levels correlating with advanced disease stage and poorer response to chemotherapy, enabling stratification of patients for personalized treatment approaches.^[81]

Implications in Neurological and Other Disorders

Dysregulation of extracellular signal-regulated kinases (ERKs), particularly ERK1/2, contributes to the pathogenesis of Alzheimer's disease by promoting tau hyperphosphorylation through activation of key kinases such as cdk5, p53, and GSK-3β, as well as modulation of protein phosphatase 2A activity.^[82] This sustained ERK1/2 signaling exacerbates neurofibrillary tangle formation and neuronal dysfunction in affected brain regions. In Parkinson's disease, ERK1/2 and ERK5 play neuroprotective roles by enhancing the basal survival of dopaminergic neurons and providing protection against oxidative stress induced by toxins like 6-hydroxydopamine.^[83] Inhibition of these pathways reduces neuron viability, underscoring their essential function in maintaining substantia nigra integrity during disease progression. Similarly, in cerebral ischemia-reperfusion injury, ERK signaling modulates excitotoxicity by regulating NMDA receptor subunits; activation of the ERK/DAPK1 pathway inhibits GluN2B phosphorylation, reducing infarct size and improving neurological outcomes in rodent models.^[84] In cardiovascular disorders, ERK5 deletion attenuates pressure overload-induced cardiac hypertrophy by impairing MEF2-dependent remodeling, though it concurrently heightens apoptosis via p53 upregulation, leading to worsened long-term cardiac function.^[85] ERK5 dysfunction also promotes atherosclerosis by disrupting endothelial integrity and vascular homeostasis.^[86] For ERK1/2, enhanced activation in hypertensive models, such as desoxycorticosterone acetate-salt hypertension, drives sex-specific vascular hyperreactivity through downregulation of mitogen-activated protein kinase phosphatase 1, resulting in elevated blood pressure and contractile responses in arterial tissues.^[87] Beyond neurological and cardiovascular contexts, ERK signaling fuels inflammation in autoimmune conditions like rheumatoid arthritis, where CD5L stimulates cytokine production (e.g., IL-6, TNF-α) and fibroblast-like synoviocyte survival via ERK1/2 activation, exacerbating joint destruction. In metabolic syndrome, elevated ERK activity in adipose tissue contributes to insulin resistance by impairing adipocytokine regulation and glucose homeostasis; pharmacological inhibition of upstream MEK normalizes blood glucose and enhances insulin sensitivity in diabetic mouse models.^[88] ERKs exhibit dual roles across these disorders, often protective in acute stress scenarios—such as promoting neuronal survival during oxidative insults—but detrimental under chronic activation, where sustained signaling fosters inflammation, apoptosis, and tissue remodeling in conditions like neurodegeneration and hypertrophy.^[89] This context-dependent nature highlights the pathway's complexity in non-oncogenic pathologies.

Therapeutic Targeting

Inhibitors of the ERK Pathway

MEK inhibitors represent a primary class of pharmacological agents targeting the ERK signaling pathway by blocking the immediate upstream kinase, MEK1/2, which phosphorylates and activates ERK1/2. These inhibitors, such as trametinib (FDA-approved in 2013 for BRAF-mutant melanoma) and cobimetinib (approved in 2015), are allosteric agents that bind to a specific pocket adjacent to the ATP-binding site on MEK, inducing a conformational change that prevents RAF-mediated phosphorylation of MEK and subsequent ERK activation.^[90] This mechanism disrupts the downstream propagation of mitogenic signals without directly competing for the ATP site, offering high selectivity for MEK over other kinases.^[91] Clinical use of these inhibitors often involves combination with BRAF inhibitors to enhance pathway suppression in cancers with BRAF mutations.^[92] Direct ERK inhibitors provide an alternative approach by targeting the terminal kinase in the cascade, addressing limitations of upstream inhibition such as feedback reactivation of the pathway through relief of negative loops. SCH772984 exemplifies this class as an ATP-competitive inhibitor that binds the ERK1/2 kinase domain with high potency (IC₅₀ values of 4 nM for ERK2 and 1 nM for ERK1), blocking phosphorylation of downstream substrates like RSK and Elk-1 while exhibiting selectivity over other MAPKs.^[93] This compound effectively inhibits proliferation in cells resistant to MEK or BRAF inhibitors by preventing ERK dimerization and nuclear translocation.^[94] Similarly, temuterkib (LY3214996), with an IC₅₀ of approximately 5 nM for both ERK1 and ERK2, functions as an ATP-competitive agent that shows blood-brain barrier penetration, enabling potential applications in neurological contexts, and overcomes adaptive resistance mechanisms in tumor cells.^[95] Upstream targeting extends to BRAF inhibitors like vemurafenib, which selectively inhibit mutant BRAF^V600E (IC₅₀ ~30 nM), thereby reducing MEK activation and indirect ERK signaling in BRAF-driven malignancies.^[96] Vemurafenib binds the ATP-competitive site of BRAF, halting the kinase cascade at an earlier point and synergizing with MEK inhibitors to prevent paradoxical ERK activation in wild-type BRAF contexts.^[97] Complementing small-molecule inhibition, proteolysis-targeting chimeras (PROTACs) offer a degradation-based strategy for ERK elimination; for instance, certain ERK1/2-directed PROTACs, such as those linking ERK binders to E3 ligase recruiters like cereblon, induce ubiquitination and proteasomal degradation of ERK proteins, achieving sustained pathway suppression beyond reversible inhibition.^[98] These bifunctional molecules demonstrate dose-dependent degradation (e.g., >90% ERK2 reduction at nanomolar concentrations) and inhibit proliferation in MAPK-dependent cancer models.^[99] For the ERK5 isoform, which diverges structurally from ERK1/2 and contributes to non-canonical signaling, isoform-specific inhibitors are under development to avoid off-target effects on the classical pathway. Selective ERK5 inhibitors are being explored in preclinical and early clinical stages for therapeutic modulation in inflammatory diseases by targeting its unique ATP site and preventing autophosphorylation essential for activation. As of 2025, advancements emphasize dual MEK/ERK inhibitors, such as novel series targeting both kinases simultaneously, to circumvent paradoxical ERK reactivation in RAS-mutant resistant tumors and enhance efficacy in colorectal and other cancers.^[100] These agents, exemplified by refined allosteric-ATP competitive hybrids, demonstrate improved pathway blockade in preclinical models without inducing compensatory feedback.^[4]

Clinical Applications and Challenges

The combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, which targets the upstream ERK pathway, has been approved by the FDA for the adjuvant treatment of patients with stage III BRAF V600E-mutated melanoma following complete resection.^[101] In the phase III COMBI-AD trial, this regimen demonstrated a 3-year overall survival rate of 86% compared to 77% with placebo, highlighting its efficacy in improving long-term outcomes in this setting.^[102] Clinical trials of ERK inhibitors have shown modest activity in NRAS-mutant cancers, particularly melanoma. In the phase III NEMO trial of the MEK inhibitor binimetinib in NRAS-mutant melanoma, the objective response rate was 15%, with median progression-free survival of 2.8 months, indicating potential but limited single-agent efficacy.^[103] For ERK5 targeting in heart failure, preclinical studies have demonstrated cardioprotective effects through activation or modulation of the ERK5 pathway to reduce hypertrophy and improve function, with early-phase trials exploring selective ERK5 inhibitors transitioning from these models, though clinical data remain preliminary.^[104] Therapeutic targeting of the ERK pathway faces significant challenges, including toxicity profiles characterized by rash and diarrhea, which occur in over 50% of patients on MEK/ERK inhibitors and often require dose adjustments.^[105] Resistance mechanisms frequently involve crosstalk with the PI3K pathway, where PI3K/AKT activation compensates for ERK inhibition, leading to reactivation of downstream survival signals.^[106] Additionally, paradoxical activation of the ERK pathway can occur with certain RAF/MEK inhibitors in wild-type contexts, promoting tumor growth rather than inhibition.^[107] Biomarkers for ERK pathway targeting include mutations in the pathway, which occur in approximately 30-40% of human cancers, primarily through RAS (up to 33%) and BRAF (about 8%) alterations, guiding patient selection.^[108] Companion diagnostics, such as FDA-approved PCR or next-generation sequencing assays for BRAF V600 mutations, are essential for identifying eligible patients and predicting response to ERK pathway inhibitors like dabrafenib plus trametinib.^[101] As of 2025, combinations of ERK inhibitors with immunotherapies, such as anti-PD-1 agents, show promise in enhancing antitumor immunity and overcoming resistance, as evidenced by preclinical models where ERK inhibition augments PD-1 blockade efficacy.^[109] However, challenges persist in neurological applications due to poor blood-brain barrier penetration of many ERK pathway inhibitors, limiting their utility in brain metastases or neurodegenerative disorders despite targeted designs improving CNS access in select cases.^[110]

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