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Phosphatidylinositol 4,5-bisphosphate

Phosphatidylinositol 4,5-bisphosphate, commonly abbreviated as PI(4,5)P₂ or PIP₂, is a low-abundance phospholipid that constitutes approximately 1–2 mol% of the lipids in the inner leaflet of the eukaryotic plasma membrane.^[1]^[2] It features a glycerol backbone esterified with fatty acids—typically stearic acid (18:0) at the sn-1 position and arachidonic acid (20:4) at the sn-2 position—linked to a myo-inositol headgroup that is phosphorylated at the 4- and 5-positions of the inositol ring.^[1]^[3] This structure enables PI(4,5)P₂ to serve as a key signaling molecule and regulator of membrane-associated proteins, with its biosynthesis primarily occurring through phosphorylation of phosphatidylinositol 4-phosphate (PI(4)P) by type I phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) or, less commonly, PI(5)P by PIP4Ks.^[3] PI(4,5)P₂ plays a central role in cellular signal transduction, acting as a substrate for enzymes such as phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K).^[1] Upon activation by receptors like G-protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs), PLC hydrolyzes PI(4,5)P₂ to generate the second messengers inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), which mobilize intracellular calcium and activate protein kinase C, respectively.^[1] Similarly, PI3K phosphorylates PI(4,5)P₂ at the 3-position to produce phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P₃), a pivotal mediator in pathways regulating cell growth, survival, and metabolism.^[1] These reactions highlight PI(4,5)P₂'s position as a hub in phosphoinositide signaling networks, with its levels tightly controlled by kinases and phosphatases to ensure spatiotemporal precision.^[3] Beyond signaling, PI(4,5)P₂ is essential for diverse cellular processes, including actin cytoskeleton organization, membrane trafficking, and ion channel regulation.^[1] It interacts with hundreds of proteins via specific lipid-binding domains such as pleckstrin homology (PH) and FERM domains, or through electrostatic binding to basic residues like lysines and arginines, thereby recruiting effectors to the plasma membrane.^[1]^[2] In cytoskeletal dynamics, PI(4,5)P₂ modulates proteins like neural Wiskott-Aldrich syndrome protein (N-WASP) and ezrin-radixin-moesin (ERM) to promote actin polymerization and cell motility.^[1] For membrane trafficking, PI(4,5)P₂ recruits adaptor protein 2 (AP2) and dynamin to facilitate clathrin-mediated endocytosis and supports exocytosis through SNARE complex assembly, though a 2025 study in neuroendocrine cells indicates a phosphoinositide switch from PI(4,5)P₂ to PI(4)P triggers dynamin-mediated fission while PI(4,5)P₂ inhibits pore closure.^[1]^[4] Additionally, PI(4,5)P₂ maintains the activity of ion channels such as inward-rectifier potassium (Kir) and KCNQ channels, with its depletion during signaling altering membrane excitability.^[1] Its lateral organization into nanodomains, influenced by multivalent cations and protein interactions, further amplifies these functions by creating localized high-density pools.^[2]

Introduction and Chemical Properties

Definition and cellular occurrence

Phosphatidylinositol 4,5-bisphosphate (PIP₂), also known as PtdIns(4,5)P₂, is a glycerophospholipid composed of a diacylglycerol backbone esterified to an inositol ring phosphorylated at the 4- and 5-positions.^[5] As a member of the phosphoinositide family, PIP₂ belongs to the broader class of phospholipids, which are amphipathic lipids that form the structural basis of eukaryotic cell membranes by self-assembling into bilayers.^[6] Inositol phosphates, the soluble head groups derived from phosphoinositides like PIP₂, function as second messengers in intracellular signaling cascades.^[6] PIP₂ constitutes a minor fraction of total phospholipids, typically comprising 1-2% of those in the plasma membrane, where it is highly enriched in the cytoplasmic (inner) leaflet.^[7] Beyond the plasma membrane, PIP₂ is present at lower levels in other intracellular compartments, including endosomes, the Golgi apparatus, and the nucleus.^[8] Within these membranes, PIP₂ often clusters into microdomains that facilitate localized interactions with proteins.^[7] Phosphoinositides, including PIP₂, were first identified in the 1950s through studies revealing their rapid metabolic turnover in cells.^[9] PIP₂ was recognized as a key signaling molecule in the 1980s, following the discovery that phospholipase C (PLC) hydrolyzes it to generate second messengers, marking a pivotal shift in understanding its biological roles.

Molecular structure and physical properties

Phosphatidylinositol 4,5-bisphosphate (PIP₂) has a molecular formula of C₄₇H₈₀O₁₉P₃, with a molar mass of approximately 1042 g/mol, though these values are approximate and vary depending on the specific fatty acid chains attached.^[10] The core structure consists of a glycerol backbone esterified at the sn-1 and sn-2 positions with fatty acyl chains, typically stearic acid (18:0) at sn-1 and arachidonic acid (20:4, with double bonds at positions 5Z, 8Z, 11Z, 14Z) at sn-2, while the sn-3 position is linked via a phosphate group to the 1-position of an inositol ring; this inositol is further phosphorylated at the 4- and 5-positions, conferring the bisphosphate designation.^[11] This configuration positions the hydrophobic acyl tails on one end and the highly polar, phosphorylated inositol headgroup on the other.^[12] The amphipathic nature of PIP₂, arising from its hydrophobic fatty acid tails and hydrophilic headgroup, enables its spontaneous insertion into lipid bilayers, where it preferentially localizes to the inner leaflet of the plasma membrane.^[13] The two phosphate groups impart a net negative charge of approximately -4 at physiological pH (due to the dianionic phosphates and neutral hydroxyls on the inositol), facilitating electrostatic interactions with positively charged protein domains such as polybasic motifs or PH domains.^[14] This charge distribution influences membrane curvature and protein recruitment without requiring specific lipid-protein hydrophobic contacts.^[15] PIP₂ exhibits low aqueous solubility, forming aggregates such as prolate ellipsoidal micelles in water at neutral pH, and its phase behavior in membranes is sensitive to ionic strength and divalent cations like Ca²⁺, which can induce clustering or phase separation in cholesterol-poor domains.^[16] Variations in fatty acid composition, such as the presence of the arachidonoyl chain at sn-2, enhance its role in signaling by making it a preferred substrate for phospholipase C (PLC), which hydrolyzes it more efficiently than species with other unsaturations, thereby optimizing the production of second messengers like IP₃ and diacylglycerol.^[17]

Biosynthesis and Metabolism

Synthesis pathways

Phosphatidylinositol 4,5-bisphosphate (PIP2), or PtdIns(4,5)P₂, is primarily synthesized through a sequential phosphorylation pathway starting from phosphatidylinositol (PI). In the first step, PI is phosphorylated at the 4-position by type III phosphatidylinositol 4-kinases (PI4Ks), such as PI4KIIIα, to generate phosphatidylinositol 4-phosphate (PI(4)P).^[18] This intermediate is then phosphorylated at the 5-position by type I phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) to produce PIP2.^[18] PI is initially synthesized de novo in the endoplasmic reticulum from cytidine diphosphate-diacylglycerol and inositol, and then transported to the Golgi apparatus and plasma membrane for these phosphorylation steps.^[18] The PIP5K family includes three main isoforms: PIP5Kα (64 kDa), PIP5Kβ (64 kDa), and PIP5Kγ (69 or 72 kDa, with splice variants like PIP5Kγ₆₆₁).^[19] PIP5Kα and PIP5Kβ are primarily localized to the plasma membrane and perinuclear vesicles, while PIP5Kγ associates with focal adhesions through interaction with talin.^[19] Localization of PIP5Ks to the plasma membrane is facilitated by ADP-ribosylation factor 6 (ARF6), which recruits and activates these kinases, particularly in endocytic and exocytic contexts.^[19] Synthesis of PIP2 is tightly regulated, often stimulated by receptor activation. For instance, Rho family GTPases such as RhoA and Rac1 directly bind and activate PIP5Ks, enhancing PIP2 production at sites of actin remodeling.^[19] During prolonged receptor stimulation, such as via M1 muscarinic receptors, the PI4K pathway is upregulated to regenerate PIP2 levels.^[18] Alternative routes contribute to PIP2 production under specific conditions. One pathway involves the dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P₃) at the 3-position by the phosphatase PTEN, yielding PIP2.^[20] Less commonly, PIP2 can be formed by phosphorylation of phosphatidylinositol 5-phosphate (PI(5)P) at the 4-position by type II phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks).^[21] Additionally, PIP2 can be regenerated through recycling of degradation products via the phosphoinositide cycle: after hydrolysis of PIP2 by phospholipase C to inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol, IP₃ is dephosphorylated stepwise to free inositol, which returns to the endoplasmic reticulum for reassembly into PI and subsequent phosphorylation to PIP2.^[18] This recycling maintains steady-state PIP2 pools, particularly during sustained signaling.^[18]

Degradation mechanisms and turnover

Phosphatidylinositol 4,5-bisphosphate (PIP₂) is primarily degraded through hydrolysis by phospholipase C (PLC) enzymes, which sever the phosphodiester linkage in the inositol ring to generate soluble inositol 1,4,5-trisphosphate (IP₃) and membrane-bound diacylglycerol (DAG).^[7] This reaction is mediated by multiple PLC isoforms, including PLCβ, which is activated downstream of Gq-coupled receptors via Gαq and Gβγ signaling, and PLCγ, which is recruited and phosphorylated by receptor tyrosine kinases.^[22] ^[23] An alternative degradative route involves phosphorylation at the D-3 position of the inositol ring by class I phosphoinositide 3-kinases (PI3Ks), transforming PIP₂ into phosphatidylinositol 3,4,5-trisphosphate (PIP₃).^[24] This modification is tightly regulated and reversible, with PIP₃ serving as a key signaling lipid before its own metabolism. PIP₂ levels are further controlled by dephosphorylation via inositol polyphosphate phosphatases targeting specific positions on the inositol headgroup. The 5-phosphatase domain of synaptojanin hydrolyzes the 5-phosphate, yielding phosphatidylinositol 4-phosphate (PI(4)P), a process critical for endocytosis.^[25] Similarly, 4-phosphatases such as INPP4A, INPP4B, and Sac2 (INPP5F) remove the 4-phosphate to produce phosphatidylinositol 5-phosphate (PI(5)P).^[26] ^[27] PIP₂ exhibits exceptionally rapid turnover in response to cellular stimuli, with half-lives as short as 4–7 seconds during intense PLC activation and up to 2 minutes in dynamic contexts like cell migration, sustained by the counterbalancing activity of kinases and phosphatases.^[28] ^[29] This flux is complemented by its synthesis from PI(4)P via type I PIP kinases.^[24]

Roles in Cellular Signaling

IP3/DAG pathway

In the IP3/DAG signaling pathway, phosphatidylinositol 4,5-bisphosphate (PIP2) functions as the key substrate for phospholipase C (PLC) enzymes, which are activated downstream of Gq-coupled G protein-coupled receptors (GPCRs). Ligand binding to these GPCRs promotes the exchange of GDP for GTP on the heterotrimeric G protein, leading to dissociation of the Gαq subunit from Gβγ; the activated Gαq then directly binds and stimulates PLCβ isoforms at the plasma membrane, catalyzing the hydrolysis of PIP2.^[30]^[31] This cleavage generates two second messengers: inositol 1,4,5-trisphosphate (IP3), a water-soluble molecule that diffuses into the cytosol, and diacylglycerol (DAG), a lipid-soluble product that remains embedded in the membrane. The bisphosphorylated inositol headgroup of PIP2 confers specificity to this enzymatic reaction, as the 4,5-phosphate positions are precisely recognized and cleaved by PLC.^[32] The hydrolysis reaction is succinctly represented as:

\text{PIP}_2 \xrightarrow{\text{PLC}} \text{IP}_3 + \text{DAG}

IP3 binds to and opens IP3 receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby mobilizing intracellular Ca²⁺ stores into the cytosol to propagate signaling. In parallel, membrane-bound DAG recruits and activates isoforms of protein kinase C (PKC), which phosphorylate downstream targets to modulate cellular responses such as gene expression and secretion. This dual-messenger system enables rapid and coordinated amplification of the initial GPCR signal. PLC isoforms exhibit distinct activation mechanisms tailored to upstream receptors, ensuring pathway specificity. PLCβ isoforms, predominant in G protein-mediated signaling, are potently activated by Gαq-GTP and, to a lesser extent, by Gβγ subunits from Gi/o-coupled GPCRs, with high affinity for the PIP2 headgroup.^[30]^[31] In contrast, PLCγ isoforms are activated by receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor, through direct tyrosine phosphorylation on specific residues (e.g., Tyr783 in PLCγ1), which relieves autoinhibition and enhances catalytic activity toward PIP2; this RTK-linked pathway often intersects with GPCR signaling in certain cellular contexts. Both isoform classes demonstrate strict substrate selectivity for PIP2 over other phosphoinositides.^[32] Hydrolysis of PIP2 is spatially compartmentalized at the plasma membrane, thereby enabling localized DAG production for PKC activation. Meanwhile, the soluble IP3 diffuses freely through the cytosol over distances of several micrometers to reach ER IP3Rs, allowing for broader intracellular Ca²⁺ wave propagation while maintaining signaling fidelity.^[33]

PI3K/Akt pathway

In the PI3K/Akt pathway, class I phosphoinositide 3-kinases (PI3Ks), which are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit, catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-position of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).^[34] This reaction occurs primarily at the plasma membrane and serves as a key lipid second messenger in signal transduction, as originally elucidated in foundational studies on PI3K activity. The enzymatic conversion can be represented as:

\ce{PIP2 + ATP ->[class I PI3K] PIP3 + ADP}

^[35] Activation of class I PI3K is triggered by upstream signals from receptor tyrosine kinases (RTKs), such as the insulin receptor, or G protein-coupled receptors (GPCRs), leading to recruitment of the p85 subunit to phosphorylated tyrosine residues on the receptors or via intermediary adaptors like Ras or Gβγ subunits.^[34]^[35] This localization enhances PIP3 production at specific membrane sites. The pathway is negatively regulated by the phosphatase PTEN, which dephosphorylates PIP3 back to PIP2, thereby limiting signal duration and preventing excessive activation; PTEN loss is associated with pathway hyperactivation in various pathologies.^[34]^[36] PIP3 recruits pleckstrin homology (PH) domain-containing proteins, including Akt (also known as PKB), to the membrane, where Akt is subsequently phosphorylated and activated by PDK1 and mTORC2.^[35] This activation propagates signaling cascades that promote cellular outcomes such as survival—through inhibition of proapoptotic factors like Bad—and migration, driven by localized PIP3 gradients that coordinate cytoskeletal rearrangements via effectors like Rac.^[34] Additionally, nuclear pools of PIP2 and PI3K contribute to transcriptional regulation; for instance, nuclear PI3K isoforms, such as p110β, generate PIP3 that activates Akt, enhancing ribosome biogenesis and mRNA processing to support cell growth, while IPMK-mediated phosphorylation of nuclear PIP2 influences transcription factor activity like SF-1.^[37]

Functions in Membrane and Cytoskeletal Dynamics

Endocytosis and exocytosis

Phosphatidylinositol 4,5-bisphosphate (PIP₂) plays a central role in clathrin-mediated endocytosis by recruiting key adaptor and fission proteins to the plasma membrane. Specifically, PIP₂ binds to the clathrin adaptor protein AP-2, facilitating its localization to clathrin-coated pits and enabling the capture of cargo molecules for internalization.^[38] This interaction is essential for pit formation, as PIP₂ clusters at these sites promote the assembly of the endocytic machinery. Additionally, PIP₂ contributes to the recruitment of dynamin, a GTPase that mediates membrane scission, through direct or adaptor-mediated binding that activates its GTPase activity during vesicle budding.^[39] Following fission, hydrolysis of PIP₂ by the phosphatase synaptojanin promotes uncoating of the clathrin coat, allowing the vesicle to proceed in trafficking.^[40] PIP₂ concentrations in the plasma membrane, estimated at effective levels equivalent to 4–10 μM, support these dynamic processes by providing sufficient lipid density for protein binding, with local enrichment at endocytic sites.^[41] In exocytosis, PIP₂ is crucial for vesicle priming and fusion, particularly in synaptic release. It binds to the priming protein CAPS (Ca²⁺-dependent activator protein for secretion), which organizes SNARE complexes to tether vesicles to the target membrane.^[42] This interaction facilitates the assembly of SNARE proteins, such as syntaxin-1 and SNAP-25, essential for membrane fusion during neurotransmitter release.^[43] Studies from the 1990s demonstrated that depletion of inositol phospholipids, including PIP₂, in permeabilized cells inhibits secretion, underscoring its necessity for exocytic events.^[44] Spatial gradients of PIP₂, generated by kinases like PIP5K, further regulate these processes by concentrating the lipid at fusion sites to enhance efficiency.^[45]

Cytoskeleton regulation

Phosphatidylinositol 4,5-bisphosphate (PIP₂) plays a central role in regulating the actin cytoskeleton by directly interacting with key actin-binding proteins, thereby modulating actin polymerization, stabilization, and organization at the plasma membrane. These interactions often occur through electrostatic binding of PIP₂'s negatively charged headgroup to basic motifs in target proteins, enabling localized control of cytoskeletal dynamics.^[46] PIP₂ is enriched in the inner leaflet of the plasma membrane, where it facilitates the recruitment and activation of proteins essential for actin network assembly.^[47] A prominent mechanism involves PIP₂'s activation of WASP (Wiskott-Aldrich syndrome protein) and Scar/WAVE family proteins, which stimulate the Arp2/3 complex to nucleate branched actin networks. Binding of PIP₂ to the basic domain of neuronal WASP (N-WASP) relieves its autoinhibition, allowing Cdc42-GTP to further promote Arp2/3-mediated actin filament branching and elongation. This process is critical for the formation of dynamic structures like lamellipodia, where branched actin networks drive membrane protrusion during cell migration. Seminal studies from the late 1990s demonstrated that PIP₂ micelles enable N-WASP to activate Arp2/3, leading to actin comet tail formation around lipid vesicles, highlighting PIP₂'s role in spatially restricted actin assembly. PIP₂ also stabilizes F-actin by inhibiting cofilin, an actin-depolymerizing factor that severs and disassembles filaments. Through direct binding to cofilin's basic residues, PIP₂ sequesters cofilin away from actin filaments, preventing depolymerization and promoting filament persistence.^[48] This interaction was first evidenced in 1990s biochemical assays showing that PIP₂ inhibits cofilin-actin binding, thereby maintaining cortical actin integrity.^[48] Additionally, PIP₂ binds to ERM (ezrin-radixin-moesin) proteins like ezrin via electrostatic interactions with their positively charged N-terminal domains, linking the actin cytoskeleton to the membrane and facilitating force transmission.^[49] Structural mapping in the 2000s confirmed that PIP₂ binding to ezrin's basic motifs induces conformational changes necessary for actin cross-linking.00447-5) PIP₂ often forms transient clusters in the membrane, enhancing local actin polymerization by concentrating effectors like N-WASP and profilin-actin complexes. These clusters drive near-membrane actin assembly, as observed in fluorescence microscopy studies where PIP₂ enrichment correlates with branched actin structures.^[50] Experimental depletion of PIP₂, such as through phospholipase C activation or nanosecond pulsed electric fields, leads to rapid actin cytoskeleton disassembly and cortical collapse, underscoring its essential stabilizing function.^[51] Early 1990s work linking PIP₂ hydrolysis to actin-binding protein dissociation provided foundational evidence for these regulatory links.^[52]

Interactions with Ion Channels and Receptors

Modulation of ion channels

Phosphatidylinositol 4,5-bisphosphate (PIP₂) plays a critical role in regulating the activity of inward rectifier potassium (Kir) channels, such as Kir2.1, by directly binding to their cytosolic domains through electrostatic interactions between the negatively charged phosphate groups of PIP₂ and positively charged residues like lysines and arginines in the channel's intracellular regions.^[53] This binding stabilizes the open conformation of the channel, enhancing its conductance and open probability, while depletion of PIP₂ leads to channel closure and inhibition of activity.^[53] For instance, in Kir2.1, key binding residues include K50, R67, and R218, which facilitate this interaction at the interface between transmembrane and cytosolic domains.^[53] Beyond potassium channels, PIP₂ activates certain transient receptor potential (TRP) channels, including members of the TRPC subfamily, by interacting with their intracellular domains to promote opening.^[54] In TRPC6, for example, PIP₂ disrupts inhibitory interactions with calmodulin, thereby facilitating channel activation.^[54] PIP₂ modulates sodium channels indirectly, primarily through its involvement in phosphoinositide signaling that affects channel trafficking and phosphorylation, though it directly enhances the activity of epithelial sodium channels (ENaC) by increasing open probability via binding to the cytoplasmic N-terminus.^[41] The regulatory mechanism of PIP₂ on these channels involves specific interactions of its headgroup with basic amino acid clusters in the channels' cytosolic domains, which are highly sensitive to PIP₂ hydrolysis by phospholipase C (PLC), resulting in rapid depletion and subsequent channel inhibition.^[55] Evidence from electrophysiological studies, particularly inside-out patch-clamp recordings, demonstrates that channel activity runs down upon excision due to PIP₂ loss, but supplementation with soluble PIP₂ analogs restores currents in a dose-dependent manner, confirming PIP₂'s direct role.^[56] For Kir channels, such experiments show partial recovery of K⁺ currents after PIP₂ application to the cytoplasmic face.^[56]

Regulation of G protein-coupled receptors and kinases

Phosphatidylinositol 4,5-bisphosphate (PIP₂) plays a critical role in stabilizing the active conformations of G protein-coupled receptors (GPCRs), particularly class A receptors such as the β₂-adrenergic receptor (β₂AR). By interacting with specific residues on the intracellular loops and transmembrane helices, PIP₂ anchors the third intracellular loop (ICL3) in an open conformation, reducing its interactions with other loops (ICL1 and ICL2) that favor inactive states.^[57] This stabilization enhances the receptor's ability to adopt the active state upon agonist binding, as demonstrated by molecular dynamics simulations showing increased PIP₂ density near TM5/TM6/ICL3 in active β₂AR ensembles.^[57] Similarly, for the β₁-adrenergic receptor (β₁AR), PIP₂ binding increases by approximately 31% in the agonist-bound state compared to the inactive form, with key hotspots on TM1, TM4, and TM7-H8.^[58] PIP₂ further facilitates G protein coupling by bridging the receptor and Gα subunits, improving signaling selectivity and efficiency. In the β₁AR:mini-G_s complex, the presence of two PIP₂ molecules enhances complex formation by 2.7-fold, while three molecules increase it by 4.5-fold, primarily through interactions with residues like Thr40 and Arg380 on Gα_s.^[58] For the neurotensin receptor 1 (NTSR1), PIP₂ boosts Gα_iβγ GTPase activity by 1.3-fold, underscoring its role in promoting productive G protein interactions.^[58] This mechanism is particularly relevant in G_q-coupled receptor activation, where PIP₂ supports initial signaling before hydrolysis.^[58] In the context of receptor desensitization, PIP₂ serves as a docking site for G protein-coupled receptor kinase 2 (GRK2) via its pleckstrin homology (PH) domain, recruiting the kinase to agonist-bound GPCRs at the plasma membrane. The PH domain binds PIP₂ and free Gβγ subunits in a coordinated manner, enabling GRK2 to phosphorylate serine/threonine residues on the receptor's C-terminal tail and intracellular loops.^[59] This phosphorylation promotes β-arrestin binding, which uncouples the receptor from G proteins, terminates signaling, and initiates internalization.^[59] Upon G_q-coupled receptor activation, phospholipase C-mediated PIP₂ hydrolysis to inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol contributes to desensitization by depleting local PIP₂ levels, thereby limiting further GRK2 recruitment and sustaining feedback inhibition. Studies from the 2000s provided key evidence for these interactions, showing that mutations in the GRK2 PH domain, such as K567E/R578E, disrupt PIP₂ and anionic phospholipid binding, abolishing receptor phosphorylation in cellular assays and impairing desensitization.^[60] These findings highlight PIP₂'s dual role in both activating and terminating GPCR signaling through conformational stabilization and kinase regulation.

Regulation and Physiological Significance

Enzymatic and environmental control

The levels of phosphatidylinositol 4,5-bisphosphate (PIP2) are tightly maintained through a dynamic enzymatic balance between synthesizing kinases and degrading phosphatases, ensuring steady-state concentrations essential for cellular functions. Phosphatidylinositol 4-kinase (PI4K) generates phosphatidylinositol 4-phosphate (PI4P), the primary substrate for PIP2 synthesis, while phosphatidylinositol 4-phosphate 5-kinase (PIP5K) isoforms, particularly PIP5Kα and PIP5Kγ, phosphorylate PI4P at the 5-position of the inositol ring to produce PIP2 predominantly at the plasma membrane.^[19] On the opposing side, 5-phosphatases such as synaptojanin hydrolyze the 5-phosphate from PIP2 to yield PI4P, facilitating membrane remodeling during endocytosis, while phosphatase and tensin homolog (PTEN) primarily dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the 3-position but indirectly influences PIP2 pools by shifting the phosphoinositide equilibrium away from 3-phosphorylated species.^[61] This balance is further refined by feedback loops, including calcium ion (Ca²⁺)-mediated inhibition of phospholipase C (PLC), which hydrolyzes PIP2 into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG); elevated Ca²⁺ levels from IP3-induced release can suppress sustained PLC activity, preventing excessive PIP2 depletion and promoting replenishment.^[62] Environmental cues modulate PIP2 levels by altering enzyme activities or substrate availability, integrating extracellular signals with lipid homeostasis. Growth factors like epidermal growth factor (EGF) activate PIP5K through downstream phosphorylation events, such as PKC-mediated targeting, thereby elevating local PIP2 synthesis to support receptor signaling and cytoskeletal responses.^[63] Cell stress conditions, including hypoxia, dynamically alter PIP2 pools; for instance, oxygen deprivation inhibits PI4K activity via ATP depletion and redox changes, leading to reduced plasma membrane PIP2 and disrupted protein targeting.^[64] Additionally, physicochemical factors like pH influence PIP2's ionization state—its phosphate groups have pKa values around 6.7 and 7.5, so acidic shifts protonate PIP2, reducing its negative charge and impairing interactions with positively charged effectors—while membrane curvature recruits or activates curvature-sensing enzymes like synaptojanin, accelerating PIP2 hydrolysis at invaginating sites during vesicle formation.^[65]^[25] Spatial regulation ensures compartment-specific PIP2 gradients, with enzymes localized to distinct cellular locales. For example, PIP5K isoforms exhibit nuclear localization, such as PIP5Kα in the nucleoplasm, where they generate PIP2 to modulate transcription factor activity and chromatin dynamics independently of plasma membrane pools.^[66] Quantitative models of PIP2 homeostasis often employ Michaelis-Menten kinetics to describe steady-state levels, where the rate of PIP2 synthesis by PIP5K follows v = \frac{V_{\max} [PI4P]}{K_m + [PI4P]}, balanced against degradation rates; such approaches reveal that PIP2 concentrations (typically 1-5% of plasma membrane phospholipids) are maintained near the Km for many effectors, allowing sensitive responses to flux perturbations.^[67]

Involvement in diseases and recent discoveries

Mutations in the PI3K pathway, particularly in PIK3CA, lead to constitutive activation of PIP3 production from PIP2, promoting uncontrolled cell proliferation and survival in various cancers, including breast, colorectal, and endometrial tumors.^[35]^[68] Deficiencies in phospholipase C (PLC), especially PLCγ2 variants, disrupt PIP2 hydrolysis into IP3 and DAG, resulting in immune dysregulation syndromes such as PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), characterized by recurrent infections, autoimmunity, and cold-induced urticaria.^[69]^[70] In Parkinson's disease, mutations in synaptojanin 1, a PIP2 phosphatase, impair synaptic vesicle endocytosis by altering PIP2 levels at presynaptic terminals, leading to accumulation of clathrin-coated vesicles and dopaminergic neuron degeneration.^[71]^[72] Therapeutic interventions targeting PIP2-related pathways include PI3K inhibitors that block the conversion of PIP2 to PIP3, thereby attenuating oncogenic signaling. Idelalisib, a selective PI3Kδ inhibitor, has been approved for relapsed chronic lymphocytic leukemia and follicular lymphoma, inducing apoptosis in malignant B cells by inhibiting AKT activation downstream of PIP3.^[73]^[74] For channelopathies involving PIP2-dependent ion channels, such as Andersen-Tawil syndrome linked to KCNJ2 mutations, strategies to enhance PIP2-channel interactions are under exploration, though clinical analogs remain preclinical.^[75] Recent discoveries have expanded the pathological roles of PIP2 beyond plasma membranes. Post-2020 studies reveal nuclear PIP2 as a regulator of chromatin dynamics and gene expression, where it modulates histone modifications and transcription factor activity, potentially contributing to cancer and developmental disorders through altered nuclear signaling.^[76]^[77] In neurodegeneration, PIP5Kγ, which synthesizes PIP2, is implicated in amyotrophic lateral sclerosis (ALS) via C9orf72 haploinsufficiency, where reduced PIP2 levels disrupt endosomal trafficking and motor neuron survival.^[78] Emerging research from 2022–2024 highlights PIP2's role in immune synapse formation, particularly in T cells, where phosphatidylinositol transfer protein Nir3 replenishes PIP2 at the immunological synapse to sustain TCR signaling and T cell activation.^[79] A 2025 study elucidated the structural basis of PIP2 activation of the sodium-calcium exchanger NCX1 through conformational changes at the transmembrane-cytosolic interface, highlighting its importance in cellular calcium regulation.^[80]

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(PDF) Salt-dependent phase behaviour of the phosphatidylinositol 4 ...
We found that the PIP2 aggregates from prolate ellipsoidal micelles at pH 7.2 and that the addition of a small amount of Ca2+ ions even below 5 mmol dm–3([Ca2+] ...<|control11|><|separator|>
[16]
How is the acyl chain composition of phosphoinositides created and ...
A preference for C38:4 substrates has been observed with CDS2 [17] and other PI cycle enzymes, such as DGKε [74] and PI4P5Ks [75], and an interesting idea ...
[17]
Phosphatidylinositol 4,5-bisphosphate is regenerated by speeding ...
Nov 13, 2020 · The simplified phosphoinositide cycle comprises synthesis of phosphatidylinositol in the ER, transport, and phosphorylation in the Golgi and ...
[18]
PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions
Nov 1, 2009 · In this Commentary, we review how PIP5Ks are modulated to achieve regulated PtdIns(4,5)P 2 production, and discuss the role of these proteins in different ...
[19]
PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K
Oct 19, 2017 · PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function ...
[20]
The mechanism of Gαq regulation of PLCβ3-catalyzed PIP2 hydrolysis
Phospholipase Cβ (PLCβ) enzymes cleave phosphatidylinositol 4,5-bisphosphate (PIP2) in the plasma membrane to produce inositol triphosphate (IP3) and ...
[21]
Structure and Roles of Phospholipase C (PLC), Phosphatidylinositol ...
Mar 27, 2025 · PLC in eukaryotic cells converts phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3), and diacylglycerol, a ...<|control11|><|separator|>
[22]
Phosphatidylinositol-4,5-bisphosphate: Targeted Production and ...
PI4,5P2 is utilized by PI3K or PLC to generate second messengers: PI3,4,5P3, DAG and IP3. The generation of PI4,5P2 in a spatio-temporal manner is the basis ...
[23]
Synaptojanin 1-mediated PI(4,5)P2 hydrolysis is modulated by ...
Our study raises the possibility that geometry-based mechanisms may contribute to spatially restricting PI(4,5)P 2 elimination during membrane internalization.
[24]
Sac2/INPP5F is an inositol 4-phosphatase that functions in the ...
Apr 13, 2015 · As the Sac domain of synaptojanin acts on PI4P and not on PI(4,5)P2, it may function in coordination with the 5-phosphatase module to convert PI ...
[25]
25 Years of PI5P - Frontiers
Oct 1, 2023 · ... PI5P through dephosphorylation of PI(4,5)P2. In fact, the group led by Philip Majerus identified two mammalian PI(4,5)P2 4-phosphatases that ...
[26]
Biophysical physiology of phosphoinositide rapid dynamics and ...
May 18, 2022 · Said differently, when endogenous PLCβ is strongly activated, the expected half-life of any given cellular PtdIns(4,5)P2 molecule is only 4–7 s.
[27]
Rapid Turnover Rate of Phosphoinositides at the Front of Migrating ...
The concentrations of phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol ... The half-life of PI(4,5)P2 was estimated to be ≈2 min (Figure 4 ...
[28]
Regulation of Polyphosphoinositide-specific Phospholipase C ...
Smrcka et al. ,. Regulation of Polyphosphoinositide-specific Phospholipase C Activity by Purified Gq.Science251,804-807(1991).DOI:10.1126/science.1846707 ...
[29]
Activation of the β1 isozyme of phospholipase C by α ... - Nature
Apr 11, 1991 · This is due to activation of phosphoinositide-specific phospho-lipase(s) C (PLC), the isozymes of which are classified into groups, α, β, γ and ...
[30]
Structure, Function, and Control of Phosphoinositide-Specific ...
Various features of the polar head group affect substrate preference. Although the prokaryotic forms of PLC prefer phosphatidylinositol (PI) and PI-glycans, the ...<|control11|><|separator|>
[31]
Localisation of Intracellular Signals and Responses during ... - MDPI
Feb 1, 2023 · Cholesterol-enriched rafts might restrict the free diffusion of PIP2 such that the metabolism of PI(4,5)P2 is compartmentalised into plasma- ...
[32]
Targeting PI3K/Akt signal transduction for cancer therapy - Nature
Dec 16, 2021 · In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and ...
[33]
PI3K/AKT/mTOR signaling transduction pathway and targeted ...
Aug 18, 2023 · The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and ...
[34]
PTEN and the PI3-Kinase Pathway in Cancer - PMC - PubMed Central
Class IA PI3Ks are activated by growth factor receptor tyrosine kinases (RTKs), whereas class IB PI3Ks are activated by G protein–coupled receptors (GPCRs) (1).The Role Of Pten... · Pten-Regulatory Domains · Other Pi3-Kinase Pathway...<|control11|><|separator|>
[35]
Nuclear PI3K signaling in cell growth and tumorigenesis - PMC
Apr 13, 2015 · The nuclear speckle localization of PI(4,5)P2, its kinases, and PI3K isozymes suggest a role of the nuclear PI3K pathway in gene transcription ...Nuclear Pi(3,4,5)p... · Regulation Of Mrna... · Ribosome BiogenesisMissing: seminal papers
[36]
Identification of postsynaptic phosphatidylinositol-4,5-bisphosphate ...
Jun 13, 2017 · Phosphatidylinositol-4,5-bisphosphate (PIP2), one of the key phospholipids, directly interacts with several membrane and cytosolic proteins ...Missing: history | Show results with:history
[37]
Regulation of presynaptic phosphatidylinositol 4,5-biphosphate by ...
... PIP2 signal seen within stimulated boutons. Degradation of PIP2 by synaptojanin then occurs, allowing the uncoating of vesicles and their repriming for ...
[38]
PIP2 is a necessary cofactor for ion channel function: How and why ...
PIP2 is found principally in the plasma membrane. Although it is the most abundant poly-phosphoinositide there, it is still only 1% of the acidic lipid in the ...Missing: percentage | Show results with:percentage
[39]
CAPS drives trans-SNARE complex formation and membrane fusion ...
CAPS proteins contain a central PH domain and are recruited to membrane PI 4,5-P2 (27), which itself is essential for priming vesicle exocytosis (28). To ...
[40]
Role of PI(4,5)P2 in Vesicle Exocytosis and Membrane Fusion - PMC
CAPS and Munc13 proteins, which bind PI(4,5)P2 and function in vesicle priming to organize SNARE proteins, are key candidates as effectors for the role of PI(4, ...
[41]
Evidence that the inositol phospholipids are necessary for ... - NIH
Evidence that the inositol phospholipids are necessary for exocytosis. Loss of inositol phospholipids and inhibition of secretion in permeabilized cells caused ...
[42]
Coupling exo- and endocytosis: An essential role for PIP2 at the ...
Aug 6, 2025 · During the first minutes PIP2 rapidly increases in a PIP5K-dependent manner forming nanoclusters. PTEN contributes to a second phase of PIP2 ...
[43]
Mechanistic principles underlying regulation of the actin ... - PNAS
Oct 9, 2017 · These findings uncover molecular principles by which membrane phosphoinositides regulate dynamics and architecture of the actin cytoskeleton in cells.Missing: seminal | Show results with:seminal
[44]
PI(4,5)P2: signaling the plasma membrane - Portland Press
Nov 11, 2022 · The actin cytoskeleton regulates cellular processes ranging from endocytosis to cell motility to cytokinesis, and it is tightly associated with ...<|control11|><|separator|>
[45]
Phosphoinositide binding and phosphorylation act sequentially in ...
Mar 1, 2004 · This indicates that PIP2− ezrin cannot bind to the actin cytoskeleton ... Binding of ezrin to PIP2 is required for its function in epithelial cell.
[46]
Live cell imaging of membrane / cytoskeleton interactions and ...
Sep 10, 2014 · ... PIP2 transport regulates the actin polymerization as well as the protrusion dynamics. Moreover, both actin polymerization driven membrane ...Pip2 And F-Actin... · Pip2 And Actin: Vesicular... · Membrane Surface Topology...
[47]
nsPEF-induced PIP2 depletion, PLC activity and actin cytoskeletal ...
Nov 11, 2016 · We demonstrate that phosphatidylinositol-4,5-bisphosphate (PIP2) depletion and hydrolysis are critical steps in the chain reaction leading to ...Missing: collapse | Show results with:collapse
[48]
The Actin-Binding Protein Profilin Binds to PIP 2 and Inhibits Its ...
Abstract. Profilin is generally thought to regulate actin polymerization, but the observation that acidic phospholipids dissociate the complex of profilin and ...
[49]
Interplay Between Lipid Modulators of Kir2 Channels: Cholesterol ...
Sep 28, 2014 · In contrast to cholesterol, the dominant effect of PIP2 on Kir channels is activation that is attributed to stabilizing the channels in the open ...
[50]
Modulation of TRPs by PIPs - PMC - PubMed Central
In most cases, PIP2 promotes TRP channel activation. Here we provide a brief overview of current insights and controversies about the mechanisms and structural ...
[51]
Alterations in Conserved Kir Channel-PIP2 Interactions Underlie ...
These results indicate that although neutralization of the Kir1.1 residue equivalent to the Kir2.1 residue K188 showed no significant effects on channel-PIP2 ...
[52]
Structural basis of PIP2 activation of the classical inward rectifier K+ ...
The K+ currents can be restored partially by exposing the cytoplasmic face of the patch to the short-chain derivative of PIP2 in a dose-dependent manner17,18 ( ...
[53]
Cellular lipids regulate the conformational ensembles of the ...
Jun 21, 2024 · We show that the lipid phosphatidylinositol 4,5-bisphosphate (PIP2), stabilizes the active state of β2-adrenergic receptor by keeping ICL3 in an open ...
[54]
PIP2 stabilises active states of GPCRs and enhances the selectivity ...
Jan 11, 2019 · To investigate the dependence of PIP2 binding on receptor conformation we incubated PIP2 with β1AR (co-purified with the agonist isoprenaline) ...
[55]
The complex G protein-coupled receptor kinase 2 (GRK2 ...
The C-terminal region of GRK2 contains a pleckstrin homology domain (PH) with binding sites for the membrane phospholipid PIP2 and free Gβγ subunits and ...
[56]
enhanced G protein-coupled receptor kinase (GRK ... - PubMed
In this study we demonstrate that phosphatidylinositol 4, 5-bisphosphate (PIP2) enhances GRK5-mediated beta-adrenergic receptor (betaAR) phosphorylation.
[57]
Striking a balance: PIP2 and PIP3 signaling in neuronal health and ...
This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ), and phosphatidylinositol 3,4,5-trisphosphate ...
[58]
Phospholipase C in Living Cells | Journal of General Physiology
The β isoform, PLCβ, is activated by G protein–coupled receptors that couple through G proteins of the Gq family by direct action of GαqGTP (Smrcka et al., 1991) ...
[59]
Phosphorylation of phosphatidylinositol 4-phosphate 5-kinase γ by ...
3.5. EGF-induced S555 phosphorylation of PIP5Kγ90, but not of PIP5Kγ87, specifically reduces talin binding and PIP2 levels. PIP5Kγ87 isoform does not bind ...
[60]
Hypoxia controls plasma membrane targeting of polarity proteins by ...
Our studies reveal a potential regulatory mechanism that dynamically controls PM PI4P and PIP2 levels in response to hypoxia and ATP inhibition.
[61]
Calcium Directly Regulates Phosphatidylinositol 4,5-Bisphosphate ...
Feb 8, 2017 · Here, we study the direct interaction of Ca 2+ with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), the main lipid marker of the plasma membrane.Missing: amphipathic | Show results with:amphipathic
[62]
Phosphatidylinositol-4-phosphate 5-Kinase 1α Modulates ... - NIH
Although there have been some reports on the role of PIP2 in the nucleus, only a few studies have documented spatial and functional characterization of PIP5K in ...
[63]
Kinetics of PIP2 metabolism and KCNQ2/3 channel regulation ...
We measured and developed a quantitative description of these metabolic and protein interaction steps by perturbing the PIP2 pool with a voltage-sensitive ...
[64]
PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics
According to various studies, the mutation frequency of the PIK3CA gene ranges from 11% to 14% in cancer. PIK3CA activation mutations are identified in multiple ...
[65]
The role of PLCγ2 in immunological disorders, cancer, and ...
Oct 13, 2020 · As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neuro- degeneration, and immune disorders. The diverse ...
[66]
Cold Urticaria, Immunodeficiency, and Autoimmunity Related to ...
Jan 11, 2012 · We propose the term PLAID (PLCγ2-associated antibody deficiency and immune dysregulation) to describe this unique constellation of clinical, ...
[67]
Parkinson's disease gene, Synaptojanin1, dysregulates the surface ...
Aug 8, 2024 · Parkinson Sac domain mutation in Synaptojanin 1 impairs clathrin uncoating at synapses and triggers dystrophic changes in dopaminergic axons.
[68]
Parkinson's disease gene, Synaptojanin1, dysregulates the surface ...
Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes ...
[69]
Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of ...
PI3K catalytic subunit mediates phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to yield phosphatidylinositol-3,4,5-trisphosphate (PIP3), a ...Pi3k Isoforms And Expression · Pi3kδ Regulation And... · Clinical Studies
[70]
Development and Clinical Applications of PI3K/AKT/mTOR Pathway ...
Jan 3, 2024 · Idelalisib, also known as CAL-101 or GS-1101, is a selective inhibitor of the PI3Kδ isoform. It was approved by the Food and Drug Administration ...
[71]
PIP2 Activates KCNQ Channels, and Its Hydrolysis Underlies ...
Here we show that a common feature of all KCNQ channels is their activation by the signaling membrane phospholipid phosphatidylinositol-bis-phosphate (PIP2). We ...
[72]
Phosphoinositide signaling in the nucleus: Impacts on chromatin ...
Dec 20, 2024 · This review highlights key discoveries on how PPIns modulate nuclear factors activity and might impact chromatin to modify gene expression.
[73]
Nuclear phosphoinositide regulation of chromatin - PMC - NIH
This review focuses on the nuclear phospholipid functions and the activities of phospholipid signaling enzymes that regulate metazoan chromatin and gene ...Missing: seminal papers
[74]
Beyond PI3Ks: targeting phosphoinositide kinases in disease - Nature
Nov 14, 2022 · Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. ... PIP5K-driven PtdIns(4,5)P2 synthesis ...
[75]
The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 ...
Dec 29, 2022 · We show that a PI transfer protein (PITP), Nir3 (Pitpnm2), promotes PIP 2 replenishment following TCR stimulation and is important for T cell development.