Affinage

PIP4K2C

Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma · UniProt Q8TBX8

Length
421 aa
Mass
47.3 kDa
Annotated
2026-06-10
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIP4K2C (PI5P4Kγ) is a phosphoinositide kinase that controls intracellular lipid pools and, through them, acts as a negative regulator of growth and inflammatory signaling (PMID:27313209, PMID:36691351). Genetically it behaves as a positive regulator of PI(3,5)P2 abundance, demonstrated by the ability of Pip4k2c haploinsufficiency to rescue the neonatal lethality and lysosomal enlargement caused by loss of FIG4 (PMID:36691351), and its lipid kinase activity producing PI(4,5)P2 supports focal adhesion formation and oncogenic proliferation, migration, and invasion (PMID:36290302, PMID:40393249). A dominant theme across tissues is restraint of mTORC1: germline deletion hyperactivates mTORC1, expanding T-helper cells, depleting regulatory T cells, and driving proinflammatory cytokines in a rapamycin-reversible manner (PMID:27313209), while in the heart PIP4K2C suppresses TGFβ1/phospho-Smad3 and AKT signaling to limit hypertrophy and fibrosis, with loss exacerbating and modRNA re-expression reversing disease after transverse aortic constriction (PMID:34026458). Loss of PIP4K2C also hypersensitizes cancer cells to insulin-driven PI3K/AKT signaling, conferring liver-specific metastatic organotropism (PMID:38286827). PIP4K2C interacts with WDR73, which stabilizes the protein via the autophagy-lysosomal pathway (PMID:36290302), and with SARS-CoV-2 nsp6 to modulate virus-induced autophagic flux (PMID:40640184); it has minimal catalytic output and is a tractable target for selective small-molecule binders and PROTAC degraders (PMID:36898968).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2016 High

    Established PIP4K2C as a physiological brake on mTORC1, answering whether this lipid kinase has an organismal signaling role rather than merely a biochemical one.

    Evidence Germline Pip4k2c knockout mice with tissue mTORC1 analysis, immune profiling, and rapamycin rescue

    PMID:27313209

    Open questions at the time
    • Does not define the lipid intermediate linking PIP4K2C to mTORC1
    • Cell-autonomous vs systemic contributions to the immune phenotype not separated
  2. 2021 Medium

    Extended the mTORC1-suppressive role into the heart and connected PIP4K2C to TGFβ1/Smad3 and AKT signaling, explaining its protective role against cardiac fibrosis.

    Evidence Loss- and gain-of-function (knockout and modRNA) in TAC mouse models with phospho-AKT/Smad3 Western blotting

    PMID:34026458

    Open questions at the time
    • N-terminal motif mechanism of PIP5K1α/Smad3 regulation not structurally resolved
    • Single lab; direct biochemical link to lipid products not shown
  3. 2023 High

    Defined PIP4K2C as a positive regulator of PI(3,5)P2 in vivo via genetic interaction with FIG4, clarifying which phosphoinositide pool it controls at the organismal level.

    Evidence Triallelic genetic epistasis in Fig4-/- Pip4k2c+/- mice with lethality rescue and lysosome morphology readouts

    PMID:36691351

    Open questions at the time
    • Direct enzymatic basis for PI(3,5)P2 elevation not demonstrated
    • Relationship between PI(3,5)P2 regulation and mTORC1/fibrosis phenotypes unresolved
  4. 2022 Medium

    Identified WDR73 as a direct binding partner that controls PIP4K2C protein stability, providing a post-translational mechanism governing PIP4K2C abundance and its PI(4,5)P2-dependent functions.

    Evidence Protein microarray, GST pulldown, WDR73 KO cells, podocyte conditional KO mice, PI(4,5)P2 and focal adhesion assays

    PMID:36290302

    Open questions at the time
    • Whether WDR73 acts as an autophagy adaptor or indirectly is not defined
    • Single lab; degradation machinery not identified
  5. 2023 Medium

    Showed PIP4K2C has minimal catalytic activity yet is a tractable, degradable target, reframing it toward a potential scaffolding function.

    Evidence Biochemical selectivity profiling, selective binder (TMX-4102) and PROTAC degrader (TMX-4153) of endogenous protein

    PMID:36898968

    Open questions at the time
    • Scaffolding role inferred, not directly demonstrated
    • Functional consequences of degradation in disease models not tested here
  6. 2024 High

    Linked PIP4K2C loss to insulin/PI3K/AKT hypersensitivity and liver metastatic organotropism, connecting its signaling-suppressive role to cancer dissemination.

    Evidence In vivo CRISPR-Cas9 screens, PI3K/AKT assays, PI3K inhibitor and SGLT2 inhibitor/ketogenic diet rescue, patient data concordance

    PMID:38286827

    Open questions at the time
    • Mechanism by which lipid pools tune insulin/AKT sensitivity not detailed
    • Whether catalytic vs scaffolding function drives metastasis unresolved
  7. 2025 Medium

    Implicated PIP4K2C in SARS-CoV-2 infection through nsp6 binding and regulation of autophagic flux, demonstrating pharmacological tractability in an antiviral context.

    Evidence Proteomics, lipidomics, single-cell transcriptomics, target engagement, antiviral and autophagic flux assays in lung organoids with RMC-113 inhibition

    PMID:40640184

    Open questions at the time
    • Direct mechanism connecting nsp6 binding to flux impairment not resolved
    • Single lab; relative contributions to entry, replication, and egress not dissected
  8. 2025 Low

    Confirmed that PIP4K2C-generated PI(4,5)P2 supports breast cancer proliferation, migration, and invasion, tying its lipid kinase output to oncogenic cell behavior.

    Evidence siRNA knockdown in MDA-MB-468 and MCF7 cells with PI(4,5)P2 measurement and functional assays

    PMID:40393249

    Open questions at the time
    • Single knockdown method without rescue
    • No pathway placement or mechanistic follow-up
    • Apparent oncogenic role contrasts with tumor-suppressive metastasis findings; context dependence unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether PIP4K2C's physiological functions are driven primarily by its lipid kinase activity, by scaffolding, or by its regulation of distinct phosphoinositide pools across tissues.
  • No structural model reconciling minimal catalytic activity with phenotypes
  • Mechanism linking lipid pools to mTORC1, insulin/AKT, and TGFβ outputs not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0016740 transferase activity 3
Localization
GO:0005764 lysosome 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
FIG4WDR73

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Germline deletion of Pip4k2c in mice leads to hyperactivation of mTORC1 signaling in multiple tissues, increased T-helper cell populations, decreased regulatory T cells, and elevated proinflammatory cytokines; rapamycin treatment rescued the inflammatory phenotype, placing PI5P4Kγ upstream of mTORC1 in immune regulation. Germline knockout mouse model with tissue mTORC1 signaling analysis, flow cytometry, cytokine measurement, and rapamycin rescue experiment Proceedings of the National Academy of Sciences of the United States of America High 27313209
2021 Pip4k2c inhibits TGFβ1 signaling via its N-terminal motif, acting through Pip5k1α, phospho-AKT 1/2/3, and phospho-Smad3, thereby suppressing cardiac fibrosis; loss of Pip4k2c in TAC mice exacerbates cardiac hypertrophy and fibrosis via mTORC1 hyperactivation, while modRNA-mediated Pip4k2c overexpression reverses these phenotypes. Loss-of-function (Pip4k2c knockout TAC mouse model) and gain-of-function (modified mRNA delivery in TAC mouse model) with cardiac function assessment, Western blotting for phospho-AKT, phospho-Smad3, and TGFβ1 pathway components Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 34026458
2024 Loss of Pip4k2c hypersensitizes cancer cells to insulin-mediated PI3K/AKT signaling, enabling liver-specific metastatic organotropism by exploiting the insulin-rich liver microenvironment; this was demonstrated through in vivo CRISPR-Cas9 screens and concordant metabolic changes in patient tumors. In vivo CRISPR-Cas9 loss-of-function screens, PI3K/AKT signaling assays in Pip4k2c-deficient cells, PI3K inhibitor and SGLT2 inhibitor/ketogenic diet rescue experiments in mouse metastasis models Nature cancer High 38286827
2023 Loss-of-function of PIP4K2C results in elevated abundance of PI(3,5)P2, genetically interacting with FIG4 (which reduces PI(3,5)P2); haploinsufficiency of Pip4k2c rescued the neonatal lethality and lysosome enlargement of Fig4-null mice, placing PIP4K2C as a positive regulator of PI(3,5)P2 levels. Genetic epistasis in triallelic mice (Fig4-/-, Pip4k2c+/-), lysosome morphology assessment, neonatal viability measurement G3 (Bethesda, Md.) High 36691351
2022 WDR73 physically interacts with PIP4K2C (validated by protein microarray and GST pulldown) and regulates PIP4K2C protein stability through the autophagy-lysosomal pathway; WDR73 depletion reduces PIP4K2C levels, leading to decreased PI(4,5)P2 and impaired focal adhesion formation in podocytes. Protein microarray, GST pulldown, WDR73 knockout HEK293 cells, podocyte-specific conditional knockout mice, PI(4,5)P2 measurement, focal adhesion assays Biology Medium 36290302
2023 PIP4K2C has minimal enzymatic activity but potential scaffolding roles; a highly potent and selective small-molecule binder (TMX-4102) and a bivalent PROTAC degrader (TMX-4153) were developed, demonstrating that PIP4K2C is a tractable and degradable target. Biochemical binding selectivity profiling, PROTAC-mediated targeted protein degradation of endogenous PIP4K2C Angewandte Chemie (International ed. in English) Medium 36898968
2025 PIP4K2C binds SARS-CoV-2 nonstructural protein 6 (nsp6) and regulates virus-induced autophagic flux impairment; PIP4K2C plays roles in SARS-CoV-2 entry, RNA replication, and assembly/egress; pharmacological inhibition of PIP4K2C with RMC-113 reverses autophagic flux impairment and suppresses viral replication. Proteomics, single-cell transcriptomics, lipidomics, clickable analog target engagement assay, functional antiviral assays in human lung organoids, autophagic flux functional assays Nature communications Medium 40640184
2025 PIP4K2C knockdown by siRNA reduces subcellular PI(4,5)P2 levels and suppresses proliferation, migration, and invasion of breast cancer cell lines, confirming that PIP4K2C's lipid kinase activity (phosphorylation of PI5P to PI(4,5)P2) is required for these oncogenic behaviors. siRNA knockdown of PIP4K2C in MDA-MB-468 and MCF7 cells, PI(4,5)P2 measurement, proliferation, migration and invasion assays Translational oncology Low 40393249

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system. Proceedings of the National Academy of Sciences of the United States of America 52 27313209
2021 Therapeutic Delivery of Pip4k2c-Modified mRNA Attenuates Cardiac Hypertrophy and Fibrosis in the Failing Heart. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 31 34026458
2019 PIP4K2A and PIP4K2C transcript levels are associated with cytogenetic risk and survival outcomes in acute myeloid leukemia. Cancer genetics 24 31109595
2024 Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation. Nature cancer 18 38286827
2023 Targeting the Dark Lipid Kinase PIP4K2C with a Potent and Selective Binder and Degrader. Angewandte Chemie (International ed. in English) 6 36898968
2025 PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2. Nature communications 5 40640184
2023 Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c. G3 (Bethesda, Md.) 5 36691351
2022 WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway-Mowat Syndrome. Biology 5 36290302
2024 PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2. bioRxiv : the preprint server for biology 2 38659941
2025 Downregulation of PIP4K2C inhibits the breast cancer cell proliferation, migration and invasion. Translational oncology 1 40393249
2025 Structure-Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-b]pyridines as Dual Inhibitors of the Lipid Kinases PIKfyve and PIP4K2C. Pharmaceuticals (Basel, Switzerland) 0 41011211

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