Affinage

INPP5K

Inositol polyphosphate 5-phosphatase K · UniProt Q9BT40

Length
448 aa
Mass
51.1 kDa
Annotated
2026-06-10
12 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP5K is an endoplasmic reticulum-associated inositol polyphosphate 5-phosphatase that hydrolyses PtdIns(4,5)P2 and PtdIns(3,4,5)P3 to control local phosphoinositide pools governing membrane organization and signalling (PMID:33060052). Its N-terminal catalytic domain carries this lipid phosphatase activity, while a C-terminal SKICH domain mediates protein interactions and subcellular targeting (PMID:33060052). INPP5K is recruited to ER tubules by the ER-shaping protein ARL6IP1 and concentrates in newly forming tubules, where its catalytic activity is required to maintain the tubular ER network—loss of INPP5K shifts the ER toward sheets, and a catalytically dead orthologue fails to rescue ER distribution defects (PMID:30087126). Through its control of local phosphoinositide levels, INPP5K governs diverse downstream outputs: it limits PtdIns(4,5)P2 at the IL-7Rα juxtamembrane polybasic region to permit receptor conformational dynamics, signalling, and bone-marrow B-cell differentiation (PMID:36599086); it promotes corticospinal axon growth by elevating active dephosphorylated cofilin in growth cones to drive actin polymerization and microtubule protrusion (PMID:35135857); and it supports the vasopressin–aquaporin-2 water-transport pathway in renal collecting ducts (PMID:21938401). Loss-of-function mutations in INPP5K cause a congenital muscular dystrophy characterized by reduced dystroglycan glycosylation, with INPP5K required for normal myofiber organization (PMID:28190459). INPP5K loss converges on decreased PHGDH and serine biosynthesis, and l-serine supplementation rescues the neuronal phenotype in zebrafish models (PMID:33792664).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 Medium

    Established a physiological signalling role by showing INPP5K acts within the vasopressin–aquaporin-2 axis controlling renal water handling, the first in vivo function ascribed to the gene.

    Evidence transgenic mouse overexpression with water metabolism and vasopressin-challenge assays plus mCCD cell line receptor/cAMP/AQP2 readouts

    PMID:21938401

    Open questions at the time
    • Whether the effect depends on INPP5K catalytic activity was not tested
    • No direct link to a specific phosphoinositide substrate at the AVPR2/AQP2 membrane
  2. 2017 Medium

    Connected INPP5K to human disease, defining loss-of-function mutations as causative for a congenital muscular dystrophy and linking the phosphatase to dystroglycan glycosylation and myofiber integrity.

    Evidence whole-exome sequencing of patients with zebrafish morpholino knockdown phenotyping and glycosylation biochemistry

    PMID:28190459

    Open questions at the time
    • Mechanism linking lipid phosphatase activity to dystroglycan glycosylation unresolved
    • Morpholino knockdown not complemented by genetic mutant or catalytic-dead rescue
  3. 2018 High

    Resolved how INPP5K reaches its site of action and why it matters, showing ARL6IP1-dependent recruitment to ER tubules and a catalytic requirement for maintaining tubular ER architecture.

    Evidence live ER imaging, siRNA depletion, and catalytically inactive rescue across mammalian cells and C. elegans neurons

    PMID:30087126

    Open questions at the time
    • The phosphoinositide species controlled at ER tubules not directly measured
    • How phosphoinositide turnover mechanically shapes tubules versus sheets unknown
  4. 2020 Medium

    Consolidated the domain architecture, assigning lipid hydrolysis to the N-terminal catalytic domain and localization/interaction to the C-terminal SKICH domain.

    Evidence domain and biochemical synthesis (review of experimental studies)

    PMID:33060052

    Open questions at the time
    • Review synthesis rather than primary data
    • SKICH-domain binding partners not individually enumerated
  5. 2021 Medium

    Identified a shared downstream metabolic consequence of INPP5K loss, placing PHGDH/serine-biosynthesis dysregulation in the disease pathway and providing a tractable rescue.

    Evidence unbiased proteomics on patient cells with l-serine rescue of neuronal phenotype in inpp5k zebrafish

    PMID:33792664

    Open questions at the time
    • Mechanistic link from phosphoinositide signalling to PHGDH expression unknown
    • Whether serine rescue generalizes to muscle phenotype untested
  6. 2022 Medium

    Demonstrated a gain-of-function therapeutic potential, showing INPP5K overexpression drives corticospinal axon sprouting via cofilin-dependent actin and microtubule dynamics.

    Evidence in vivo AAV overexpression across pyramidotomy, stroke, and contusion injury models with cofilin/actin growth-cone readouts

    PMID:35135857

    Open questions at the time
    • Direct phosphoinositide-to-cofilin signalling step not defined
    • Effect of physiological (non-overexpressed) INPP5K on axon growth untested
  7. 2023 Medium

    Provided the clearest mechanistic chain from substrate to phenotype, showing INPP5K limits juxtamembrane PtdIns(4,5)P2 to enable IL-7Rα conformational dynamics, signalling, and B-cell differentiation.

    Evidence INPP5K knockout/knockdown with PtdIns(4,5)P2 quantification, receptor conformational assays, EBF1/PAX5 readouts, and differentiation/proliferation assays

    PMID:36599086

    Open questions at the time
    • Single-lab study
    • Whether ER-localized or plasma-membrane INPP5K pool acts on IL-7Rα not distinguished
  8. 2023 Low

    Extended INPP5K function to ER calcium handling, implicating it in IP3 receptor-mediated Ca2+ release independent of ER store content.

    Evidence INPP5K knockdown with Ca2+ imaging in intact and permeabilized glioblastoma cells

    PMID:37842182

    Open questions at the time
    • Single cell line, single lab
    • No molecular mechanism for IP3R regulation identified
    • Catalytic requirement not tested
  9. 2024 Low

    Reinforced a role in differentiation and glycosylation in a neuronal context, paralleling the muscular dystrophy glycosylation defect.

    Evidence siRNA knockdown in N2A neuroblastoma cells with differentiation and glycosylation readouts

    PMID:38559786

    Open questions at the time
    • Single cell line without pathway placement
    • Mechanistic link between phosphatase activity and glycosylation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ER lipid phosphatase coordinates such diverse outputs—ER tubule shaping, receptor signalling, calcium release, glycosylation, and axon growth—through specific phosphoinositide pools at distinct membranes remains unresolved.
  • No unifying model linking specific substrate pools to each downstream effector
  • Spatial segregation of ER versus plasma-membrane INPP5K activity not mapped
  • Mechanism connecting phosphoinositide turnover to dystroglycan/protein glycosylation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0016787 hydrolase activity 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
ARL6IP1IL7R

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Recruitment of INPP5K to the ER is mediated by ARL6IP1, an ER-shaping protein. INPP5K is preferentially localized in ER tubules and enriched in newly formed tubules growing along microtubule tracks. Depletion of either INPP5K or ARL6IP1 results in an increase of ER sheets. In C. elegans, the INPP5K orthologue CIL-1 controls ER network distribution in dendrites, and the catalytically inactive mutant fails to rescue this phenotype, establishing that phosphatase activity is required for ER organization. Fluorescence microscopy/live imaging of ER markers, siRNA depletion, rescue with catalytically inactive mutant in C. elegans PVD neurons, genetic screen for ER distribution mutants The Journal of cell biology High 30087126
2020 INPP5K protein structure comprises an N-terminal catalytic domain that hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, and a C-terminal SKICH domain responsible for protein–protein interactions and subcellular localization. INPP5K is predominantly concentrated in the ER but also detected at the plasma membrane, in the cytosol, and nucleus. Domain analysis, biochemical characterization reviewed across multiple studies (review article synthesizing experimental data) Advances in biological regulation Medium 33060052
2011 INPP5K overexpression in kidney collecting ducts increases arginine vasopressin receptor type 2 expression and cAMP response to vasopressin, leading to increased aquaporin-2 expression and plasma membrane localization, and enhanced osmotically induced water transport, demonstrating a role for INPP5K in the vasopressin–aquaporin-2 signalling pathway. Transgenic mouse overexpression, water metabolism assays (plasma osmolality, water load test), vasopressin challenge, mCCD cell line overexpression with receptor/cAMP/AQP2 readouts Pflugers Archiv : European journal of physiology Medium 21938401
2017 Loss-of-function mutations in INPP5K cause a congenital muscular dystrophy with reduced dystroglycan glycosylation; morpholino-mediated knockdown of inpp5k in zebrafish produces shortened body axis, microphthalmia, microcephaly, reduced touch-evoked motility, and disorganized myofibers, establishing INPP5K as required for normal myofiber organization and dystroglycan glycosylation. Whole-exome sequencing of patients, morpholino knockdown in zebrafish with phenotypic analysis (body axis, eye, brain, motility, muscle histology), biochemical glycosylation assays American journal of human genetics Medium 28190459
2023 Loss of INPP5K increases levels of its substrate PtdIns(4,5)P2 at the IL-7Rα cytoplasmic juxtamembrane polybasic region, causing stronger ionic interactions that freeze IL-7Rα conformation, impair IL-7R signalling, reduce EBF1 and PAX5 expression, disrupt microdomain formation and cytoskeletal reorganization, and block bone marrow B-cell differentiation. The same mechanism reduced proliferation of leukemia-associated constitutively active IL-7Rα mutants. INPP5K knockout/knockdown, PtdIns(4,5)P2 level measurement, IL-7R structural dynamics assays, signalling pathway readouts (EBF1/PAX5), B-cell differentiation assays, cell proliferation assays with mutant IL-7Rα Blood Medium 36599086
2022 Overexpression of INPP5K in adult corticospinal neurons enhances sprouting of intact corticospinal tract axons after pyramidotomy, cortical stroke, and spinal cord contusion. INPP5K stimulates axon growth by elevating active (dephosphorylated) cofilin density in growth cones, thereby stimulating actin polymerization and promoting microtubule protrusion into distal filopodia. In vivo AAV-mediated overexpression in mice, pyramidotomy and contusion injury models, axon sprouting quantification, cofilin activity immunostaining in growth cones, in vitro cortical neuron assays The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 35135857
2023 Loss of INPP5K in glioblastoma U-251 MG cells impairs agonist-induced, IP3 receptor-mediated Ca2+ mobilization without affecting ER Ca2+ content or store-operated Ca2+ entry. IP3-induced Ca2+ release is also disrupted in permeabilized cells, suggesting INPP5K directly influences IP3 receptor activity. INPP5K knockdown, Ca2+ imaging in intact and permeabilized cells, IP3 receptor stimulation, store-operated Ca2+ entry measurement BBA advances Low 37842182
2024 Knockdown of INPP5K in N2A neuroblastoma cells impairs neuronal-like differentiation and interferes with protein glycosylation. siRNA knockdown in N2A cells, morphological differentiation assay, protein glycosylation analysis Frontiers in molecular neuroscience Low 38559786
2021 Proteomic profiling of cells from INPP5K patients and SIL1 (Marinesco-Sjögren syndrome) patients identified decreased PHGDH (d-3-phosphoglycerate dehydrogenase) as a shared molecular feature. l-serine supplementation (which compensates for reduced PHGDH activity) improved the neuronal phenotype in inpp5k zebrafish models, placing PHGDH dysregulation downstream of INPP5K loss. Unbiased proteomics on patient-derived cells, zebrafish inpp5k knockout model with l-serine treatment and neuronal phenotype rescue Brain : a journal of neurology Medium 33792664

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy. American journal of human genetics 57 28190459
2018 The inositol 5-phosphatase INPP5K participates in the fine control of ER organization. The Journal of cell biology 44 30087126
2015 Analysis of an independent tumor suppressor locus telomeric to Tp53 suggested Inpp5k and Myo1c as novel tumor suppressor gene candidates in this region. BMC genetics 23 26170120
2021 INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain : a journal of neurology 18 33792664
2018 INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family. Clinical genetics 16 28940338
2020 The phosphoinositide 5-phosphatase INPP5K: From gene structure to in vivo functions. Advances in biological regulation 11 33060052
2020 A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy. Frontiers in genetics 10 33193651
2022 Inositol Polyphosphate-5-Phosphatase K (Inpp5k) Enhances Sprouting of Corticospinal Tract Axons after CNS Trauma. The Journal of neuroscience : the official journal of the Society for Neuroscience 8 35135857
2011 The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system. Pflugers Archiv : European journal of physiology 8 21938401
2023 INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors. Blood 5 36599086
2023 Loss of INPP5K attenuates IP3-induced Ca2+ responses in the glioblastoma cell line U-251 MG cells. BBA advances 3 37842182
2024 Knockdown of INPP5K compromises the differentiation of N2A cells. Frontiers in molecular neuroscience 2 38559586

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