PIP5K1C

PIP5K1C (PIP5Kγ) is a phosphatidylinositol-4-phosphate 5-kinase that phosphorylates PI(4)P to generate PI(4,5)P2 at the plasma membrane and on membrane vesicles, supplying a localized lipid signal that governs cytoskeletal dynamics, vesicle tethering, membrane receptor signaling, and cell-fate decisions (PMID:17701898, PMID:35609603). Its catalytic activity is enhanced by SIRT1-mediated deacetylation of K265/K268 (PMID:20668706) and modulated by phosphorylation; Syk transiently activates it during phagocytosis (PMID:19153220). By controlling PI(4,5)P2 pools, PIP5K1C acts upstream of RhoA/Rac1 balance to drive Fcγ-receptor–mediated phagocytosis and integrin/RhoA-dependent neutrophil polarization, with the PIP5K1C-90 isoform delivered to uropods to provide a directional cue (PMID:19153220, PMID:20850356). At late vesicles, Arf6 recruits PIP5K1C to produce PI(4,5)P2 that drives exocyst complex recruitment and membrane tethering (PMID:35609603). PIP5K1C-derived PI(4,5)P2 also couples to IP3/Ca2+ signaling that drives neuronal and CaMK/Runx2-dependent osteoblast differentiation (PMID:21216957, PMID:35090892), supports focal-adhesion–dependent adhesion of chondrocytes (PMID:37008048), sensitizes nociceptive DRG neurons through TRPV1 and pronociceptive receptor signaling (PMID:24853942), and, via a Merlin–LATS1 complex, activates the Hippo pathway to inhibit YAP (PMID:37834234). A homozygous kinase-dead D253N mutation causes lethal congenital contractural syndrome type 3 (LCCS3) in humans by disordering the ATP-binding glycine-rich loop (PMID:17701898, PMID:29959184).

1. 2007 High

   Established PIP5K1C as a disease gene by showing that loss of its PI(4)P 5-kinase activity causes a human Mendelian syndrome, directly linking PI(4,5)P2 production to a developmental phenotype.

   Evidence Positional cloning and kinase activity assay of the D253N mutant protein causing LCCS3

   PMID:17701898

   Open questions at the time

   • Did not define the structural basis of activity loss
   • Did not identify the affected downstream developmental pathway
2. 2009 High

   Defined PIP5K1C as a regulator of the actin cytoskeleton during Fcγ-receptor phagocytosis, placing it upstream of the RhoA/Rac1 balance and downstream of Syk activation.

   Evidence Knockout macrophages, RNAi, exogenous PIP2 rescue, and RhoA/Rac1 epistasis

   PMID:19153220

   Open questions at the time

   • Mechanism by which Syk phosphorylation activates the kinase not resolved at the residue level
   • Spatial control of PI(4,5)P2 during particle attachment not defined
3. 2010 High

   Showed PIP5K1C governs leukocyte motility through integrin-dependent uropod targeting of the PIP5K1C-90 isoform and chemoattractant-induced RhoA activation, and identified SIRT1 deacetylation of K265/K268 as a direct activity-enhancing modification linked to regulated exocytosis.

   Evidence PIP5K1C knockout mice with in vivo recruitment and live vesicle imaging; LC/MS interactomics, Co-IP, in vitro deacetylation assay, and SIRT1 knockout mice

   PMID:20668706 PMID:20850356

   Open questions at the time

   • How acetylation status is dynamically set in vivo not established
   • Vesicle-transport machinery delivering the -90 isoform to uropods not defined
4. 2011 Medium

   Connected PIP5K1C expression to a cell-fate switch, showing EZH2-mediated transcriptional repression must be relieved to raise PI(4,5)P2 and IP3/Ca2+ for neuronal differentiation.

   Evidence ChIP of EZH2 at the PIP5K1C promoter with knockdown and PI(4,5)P2/Ca2+ readouts in mesenchymal stem cells

   PMID:21216957

   Open questions at the time

   • Signal triggering EZH2 loss at the promoter not identified
   • Direct chain from PI(4,5)P2 to IP3 receptor activation in this context not fully reconstituted
5. 2014 High

   Identified PIP5K1C as the dominant PI(4,5)P2 source in DRG neurons and a driver of nociceptive sensitization, validating it as a pharmacological pain target.

   Evidence Pip5k1c haploinsufficient mice with DRG lipid quantification, TRPV1 sensitization, behavioral pain models, and the UNC3230 inhibitor

   PMID:24853942

   Open questions at the time

   • Which pronociceptive receptors converge on PIP5K1C not fully enumerated
   • Contribution of CNS sites versus DRG not separated
6. 2017 Medium

   Refined the site of nociceptive action by showing DRG-selective deletion accelerates recovery from inflammatory hypersensitivity without affecting acute sensation, implying additional CNS contributions.

   Evidence Two inducible Cre lines with behavioral pain testing

   PMID:29020859

   Open questions at the time

   • CNS regions mediating residual sensitization not identified
   • Molecular target downstream of PI(4,5)P2 in sensitization recovery unresolved
7. 2018 High

   Resolved the structural basis of the LCCS3 mutation, showing D253N disorders the glycine-rich loop and ATP electrostatics to abolish catalysis without altering active-site architecture.

   Evidence X-ray crystallography of the zebrafish ortholog mutant, MD simulation, and kinase assay

   PMID:29959184

   Open questions at the time

   • Structure of the human protein-substrate complex not solved
   • How loss of activity produces the contractural developmental phenotype not mechanistically traced
8. 2018 Low

   Proposed PKD1 phosphorylation of S448 as a regulatory input controlling focal adhesion dynamics, with downregulation in breast carcinoma.

   Evidence Phospho-specific IHC in normal versus carcinoma tissue; PKD1-substrate relationship cited from prior work

   PMID:30555634

   Open questions at the time

   • Direct PKD1-mediated phosphorylation of S448 not demonstrated in this study
   • Functional consequence of S448 phosphorylation on kinase activity not measured
9. 2022 High

   Demonstrated a vesicle-tethering function in which Arf6-recruited PIP5K1C generates PI(4,5)P2 that is minimally sufficient to recruit the exocyst, mechanistically linking lipid synthesis to membrane fusion-site assembly.

   Evidence In vitro reconstitution of octameric exocyst, liposome tethering assays, and Arf6/PIP5K1C manipulation in epithelial cells

   PMID:35609603

   Open questions at the time

   • How Arf6 spatially restricts recruitment in vivo not detailed
   • Coordination with cargo selection not addressed
10. 2022 Medium

    Showed PIP5K1C controls a mesenchymal lineage decision via Ca2+/CaMK signaling that stabilizes Runx2 to favor osteoblast over adipocyte fate and supports osteoclastogenesis through RANKL.

    Evidence Prx1-Cre conditional knockout mice with histomorphometry, micro-CT, Ca2+ flux, and CaMK/Runx2 western blots

    PMID:35090892

    Open questions at the time

    • Link from PI(4,5)P2 to the Ca2+ influx channel not defined
    • Direct effect on RANKL transcription not mechanistically traced
11. 2023 Medium

    Placed PIP5K1C as a parallel PI(4,5)P2 source to PIKFYVE that sets cancer-cell sensitivity to PIKFYVE inhibition in lysosome/autophagy homeostasis.

    Evidence Knockdown/overexpression rescue with PIKFYVE inhibitor WX8, phosphoinositide mass spectrometry, and lysosome/autophagy assays

    PMID:36803256

    Open questions at the time

    • Subcellular site of the relevant PI(4,5)P2 pool not defined
    • Whether the two enzymes act on shared or distinct substrate pools unresolved
12. 2023 Medium

    Identified a Hippo-regulatory role in which the PIP5Kγ90 isoform forms a Merlin-LATS1 complex requiring catalytic activity to phosphorylate and inhibit YAP, restraining YAP-driven colony formation.

    Evidence Reciprocal Co-IP, kinase-dead mutant analysis, splice-variant expression, YAP phosphorylation, and UNC3230 colony assays

    PMID:37834234

    Open questions at the time

    • How PI(4,5)P2 production mechanistically activates LATS1 not resolved
    • Role of the Hsc70 interaction not fully defined
13. 2023 Medium

    Demonstrated PIP5K1C maintains chondrocyte adhesion via focal adhesion proteins, with loss promoting matrix degradation and spontaneous osteoarthritis-like lesions in aged mice.

    Evidence Inducible chondrocyte-specific knockout with histology, FA-protein western blots, and adhesion assays

    PMID:37008048

    Open questions at the time

    • Mechanism linking PI(4,5)P2 to integrin β1 activation in chondrocytes not detailed
    • Whether the adhesion defect is cell-autonomous in driving OA not established
14. 2024 Low

    Implicated PIP5K1C-dependent PI(4,5)P2 in ACE2-mediated SARS-CoV-2 endosomal entry.

    Evidence Dual inhibitor UNI418 treatment with viral entry and endocytosis assays

    PMID:39085352

    Open questions at the time

    • Dual-specificity inhibitor cannot isolate PIP5K1C from PIKfyve
    • No genetic loss-of-function validation
15. 2025 Low

    Indicated PIP5K1C activity opposes INPP5E-dependent phosphoinositide homeostasis required for ciliogenesis.

    Evidence PIP5K1C inhibition restoring ciliogenesis in TBC1D19-null cells (preprint)

    Open questions at the time

    • Single pharmacological experiment in a preprint, not independently confirmed
    • PIP5K1C is a secondary finding in a TBC1D19-focused study
    • No direct measurement of ciliary phosphoinositide changes attributable to PIP5K1C

• How PIP5K1C activity, isoform choice, and subcellular targeting are integrated to generate distinct PI(4,5)P2 pools for each downstream process remains unresolved.
• No unified model of how post-translational modifications and recruitment factors select among phagocytic, migratory, exocytic, Hippo, and differentiation outputs
• Endogenous regulation of S448 phosphorylation and acetylation in tissue contexts undefined