INPP5F

INPP5F (Sac2) is a phosphoinositide phosphatase that regulates membrane trafficking and growth signaling by hydrolyzing specific phosphoinositides. It specifically dephosphorylates phosphatidylinositol 4-phosphate (PI4P) in vitro through a catalytic domain whose activity is abolished by the C458S mutation, and it carries a unique PH-Sac2 module conserved across orthologues (PMID:25869669). On endocytic membranes — clathrin-coated vesicles, macropinosomes, and Rab5-positive endosomes — it is recruited in a Rab5-dependent manner and partners with OCRL, the two enzymes acting sequentially on the 5- and 4-positions of inositol to dephosphorylate PI(4,5)P2 in a manner mimicking the dual phosphatase modules of synaptojanin (PMID:25869668). Through this activity INPP5F governs membrane cargo recycling: loss of its catalytic function disrupts transferrin receptor and integrin recycling and impairs cell migration (PMID:25869669), and it localizes in a PI4P-dependent fashion to insulin granules where it controls the phosphoinositide switch required for granule docking and exocytosis (PMID:31533953). At synapses it functions partially redundantly with synaptojanin 1 in synaptic vesicle recycling, with combined loss producing synthetic lethality and accelerated dopaminergic terminal degeneration (PMID:32424101). INPP5F also acts as a negative regulator of PI3K/Akt-driven signaling: in the heart it degrades PtdIns(3,4,5)P3 to restrain hypertrophy (PMID:19875726), whereas in CNS neurons it suppresses axon regeneration through a PI3K/AKT/mTOR-independent route (PMID:26203138). Additional roles in tumor signaling — inhibition of STAT3 in glioblastoma (PMID:25476455) and a nucleocytoplasmic localization switch driving Notch activation in hepatocellular carcinoma (PMID:34996491) — extend its function beyond phosphoinositide turnover.

1. 2009 High

   Established INPP5F as an in vivo brake on cardiac hypertrophy, connecting it to growth signaling before its lipid substrate was molecularly defined.

   Evidence Reciprocal knockout and cardiac-specific overexpression mouse models with biochemical phenotyping

   PMID:19875726

   Open questions at the time

   • Direct enzymatic action on PtdIns(3,4,5)P3 inferred from pathway antagonism rather than reconstitution
   • Upstream signals controlling Inpp5f in stressed myocardium not defined here
2. 2014 Medium

   Linked INPP5F to a non-lipid signaling axis by showing it binds and suppresses STAT3 phosphorylation, restraining glioblastoma stem cell self-renewal.

   Evidence Co-immunoprecipitation, phospho-STAT3 western blot, and overexpression/knockdown tumor assays

   PMID:25476455

   Open questions at the time

   • Single Co-IP without reciprocal validation
   • Whether STAT3 inhibition depends on phosphatase activity not tested
   • No structural basis for the interaction
3. 2015 High

   Defined the core biochemistry — INPP5F is a PI4P phosphatase that, with OCRL on Rab5 endosomes, sequentially dephosphorylates PI(4,5)P2 to control endocytic recycling and migration.

   Evidence In vitro phosphatase assays, C458S catalytic-dead mutagenesis, knockout, transferrin/integrin recycling and migration assays, Co-IP, structural characterization

   PMID:25869668 PMID:25869669

   Open questions at the time

   • Precise sequence of substrate handoff between INPP5F and OCRL in cells not resolved
   • Full structure of catalytic domain not determined
4. 2015 High

   Showed INPP5F suppresses CNS axon regeneration through a mechanism distinct from PTEN/mTOR, identifying it as a regeneration brake with a different substrate logic.

   Evidence RNAi screen, shRNA silencing, knockout neuron culture, spinal cord injury model, rapamycin epistasis

   PMID:26203138

   Open questions at the time

   • The specific phosphoinositide substrate governing regeneration not identified
   • Effectors downstream of the mTOR-independent pathway unknown
5. 2016 Medium

   Placed INPP5F in a transcriptional negative-feedback loop on Akt signaling in the heart, with diabetic conditions disrupting its protective output.

   Evidence Promoter/reporter and Sp1 binding assays, p-Akt western blot, diabetic mouse models, NF-κB inhibition

   PMID:26908121

   Open questions at the time

   • No independent replication
   • Direct Sp1 occupancy at the endogenous promoter not shown
6. 2019 High

   Extended INPP5F's trafficking role to regulated secretion, showing PI4P-dependent recruitment to insulin granules controls their docking at the plasma membrane.

   Evidence Live-cell/TIRF imaging, knockout/knockdown in β cells and human islets, granule docking and exocytosis assays

   PMID:31533953

   Open questions at the time

   • The downstream tethering machinery coupled to the PI4P switch not identified
   • Relationship to OCRL at granules not addressed
7. 2019 Low

   Proposed HDAC2-mediated repression of Inpp5f as a node in neuropathic pain via PI3K/Akt/GSK-3β signaling.

   Evidence HDAC2 knockdown, Inpp5f overexpression, RT-qPCR, phospho-pathway western blots, behavioral tests in rats

   PMID:31281447

   Open questions at the time

   • HDAC2–Inpp5f link is correlative, not direct
   • Single-lab, single-method readouts without orthogonal confirmation
8. 2020 High

   Demonstrated functional overlap with synaptojanin 1 in synaptic vesicle recycling through synthetic lethality and accelerated dopaminergic pathology in double mutants.

   Evidence Double-mutant mouse genetic epistasis with neuroanatomical, biochemical, and immunocytochemical analysis

   PMID:32424101

   Open questions at the time

   • Degree of non-overlapping versus shared substrate pools at the synapse not quantified
   • Relevance to human Parkinson's disease beyond the SJ1 mutation not established
9. 2022 Medium

   Revealed a nucleocytoplasmic localization switch in which cytoplasmic INPP5F binds ASPH to activate Notch and drive hepatocellular carcinoma proliferation and glycolysis.

   Evidence Co-IP, mass spectrometry, NLS/NES mutagenesis, leptomycin B treatment, transcriptomics, in vitro and in vivo tumor models

   PMID:34996491

   Open questions at the time

   • No independent replication
   • Whether this oncogenic function requires phosphatase activity unknown
   • Mechanism connecting ASPH binding to Notch activation not dissected

• How INPP5F's phosphoinositide-phosphatase activity mechanistically connects to its non-lipid functions (STAT3 inhibition, ASPH/Notch activation) and its mTOR-independent regeneration substrate remains unresolved.
• No defined substrate for the axon-regeneration phenotype
• Catalytic dependence of tumor-signaling roles untested
• No structural model integrating PH-Sac2 and catalytic domains