Affinage

PITPNM3

Membrane-associated phosphatidylinositol transfer protein 3 · UniProt Q9BZ71

Length
974 aa
Mass
106.8 kDa
Annotated
2026-06-10
24 papers in source corpus 10 papers cited in narrative 10 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

PITPNM3 (Nir1) is a membrane-associated phosphatidylinositol-transfer protein that operates at ER–plasma membrane junctions and additionally functions as a signaling receptor for the chemokine CCL18 (PMID:35020418, PMID:21481794). At ER–PM junctions, where it constitutively localizes, PITPNM3 binds Nir2 through a region between its FFAT motif and DDHD domain and potentiates Nir2 targeting during receptor-mediated signaling, an activity required for efficient replenishment of plasma membrane PIP2 (PMID:35020418). Its LNS2 domain binds phosphatidic acid and PIP2 in vitro, with phosphatidic acid being necessary and sufficient for membrane localization (PMID:38464273). As a CCL18 receptor on epithelial cancer cells, PITPNM3 engagement triggers integrin clustering, intracellular calcium signaling, and enhanced extracellular-matrix adherence, driving invasion and metastasis (PMID:21481794); downstream of this receptor, CCL18 activates multiple effector cascades that converge on epithelial-mesenchymal transition and motility, including PI3K/Akt/GSK3β-dependent Snail stabilization and actin remodeling via LIMK/cofilin (PMID:24001613), NF-κB activation (PMID:26449829), ELMO1-dependent RAC1 and integrin β1 signaling (PMID:26756176), and JAK2/STAT3 signaling (PMID:32641093). PITPNM3 expression is transcriptionally controlled by SP1, whose activity is suppressed by Mfn-2 (PMID:31955176). A missense mutation (Q626H) in the C-terminal PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5), linking the protein to photoreceptor maintenance (PMID:17377520).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 Medium

    Established the first disease link for PITPNM3 by mapping a cone dystrophy mutation to its C-terminal PYK2-binding domain, implicating the protein in phototransduction.

    Evidence Genetic linkage refinement and direct sequencing in CORD5 families, with mutation mapped to the PYK2-interacting domain

    PMID:17377520

    Open questions at the time
    • No in vitro reconstitution of the PITPNM3–PYK2 interaction
    • Mechanism of photoreceptor maintenance not defined
    • Functional consequence of Q626H on PYK2 binding not directly tested
  2. 2011 High

    Identified PITPNM3 as a functional receptor for CCL18, answering how this chemokine drives cancer cell invasion and metastasis.

    Evidence siRNA knockdown with calcium signaling, integrin clustering, invasion assays, and breast cancer xenograft model

    PMID:21481794

    Open questions at the time
    • Structural basis of CCL18–PITPNM3 binding not resolved
    • Direct ligand-binding affinity not quantified
  3. 2013 Medium

    Defined a downstream effector route by showing CCL18–PITPNM3 stabilizes Snail and drives EMT through PI3K/Akt/GSK3β and actin-remodeling kinases.

    Evidence Western blot for phospho-Akt/LIMK/cofilin, siRNA knockdown, PI3K inhibitor (LY294002), in vivo lung metastasis model

    PMID:24001613

    Open questions at the time
    • Direct coupling between receptor and PI3K not established
    • Single lab
  4. 2015 Medium

    Extended PITPNM3 receptor signaling to NF-κB activation in a second cancer type (hepatocellular carcinoma).

    Evidence siRNA knockdown, Western blot for IKK/IκBα phosphorylation, p65 nuclear translocation, migration/invasion assays

    PMID:26449829

    Open questions at the time
    • Receptor-proximal events linking PITPNM3 to IKK not defined
    • Single lab
  5. 2016 Medium

    Connected PITPNM3 to cytoskeletal control via an ELMO1/RAC1 and integrin β1 axis in lung cancer.

    Evidence siRNA knockdown, RAC1 activation assay, ELMO1 co-signaling analysis, adhesion and invasion assays

    PMID:26756176

    Open questions at the time
    • Whether ELMO1 physically associates with PITPNM3 not shown
    • Single lab
  6. 2020 Medium

    Added JAK2/STAT3 as a CCL18–PITPNM3 effector pathway in oral squamous cell carcinoma.

    Evidence siRNA knockdown, Western blot for JAK2/STAT3 phosphorylation, JAK inhibitor AG490, proliferation/invasion/migration assays

    PMID:32641093

    Open questions at the time
    • Mechanism linking receptor engagement to JAK2 activation unresolved
    • Single lab
  7. 2020 Medium

    Identified an upstream transcriptional control mechanism, showing SP1 drives PITPNM3 expression and Mfn-2 represses it via SP1.

    Evidence Co-IP (Mfn-2/SP1), ChIP (SP1 on PITPNM3 promoter), RT-PCR, in vivo tumorigenicity in nude mice

    PMID:31955176

    Open questions at the time
    • Direct effect of Mfn-2 on PITPNM3 not separated from SP1-independent routes
    • Single study without replication
  8. 2022 High

    Defined a distinct lipid-homeostasis function, showing PITPNM3 resides at ER-PM junctions and recruits Nir2 to support PIP2 replenishment.

    Evidence Live-cell imaging, co-immunoprecipitation, domain mapping, and PIP2 replenishment assay

    PMID:35020418

    Open questions at the time
    • How junctional lipid-transfer role relates to its CCL18-receptor role not integrated
    • Tethering partners at ER-PM junctions not fully enumerated
  9. 2022 Medium

    Delimited PITPNM3's receptor role by showing that CCL18-induced microglial phagocytosis depends on CCR8, not PITPNM3.

    Evidence Selective siRNA knockdown of CCR8 vs PITPNM3, phagocytosis assays, Western blot for NF-κB/Src signaling

    PMID:35041514

    Open questions at the time
    • Cell-type specificity of CCL18 receptor usage not mechanistically explained
    • Single lab negative result
  10. 2025 Medium

    Resolved the lipid-binding basis of PITPNM3 membrane targeting, showing its LNS2 domain binds PA and PIP2 but requires PA for localization.

    Evidence Liposome binding assays and live-cell PILS-Nir1 biosensor imaging in HEK293A cells (preprint)

    PMID:38464273

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Physiological role of PA sensing in full-length PITPNM3 function not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PITPNM3's ER-PM junctional lipid-transfer activity, its CCL18-receptor signaling, and its PYK2-dependent role in photoreceptors are mechanistically unified within one protein remains unresolved.
  • No structure of full-length PITPNM3
  • No reconciliation of receptor vs lipid-transfer functions
  • PYK2-binding domain function untested biochemically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1 GO:0060089 molecular transducer activity 1 GO:0140104 molecular carrier activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 1
Partners
CCL18ELMO1NIR2PYK2

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 PITPNM3 functions as a receptor for CCL18 on breast cancer cells; CCL18 binding to PITPNM3 triggers integrin clustering, enhances adherence to extracellular matrix, activates intracellular calcium signaling, and promotes invasion and metastasis. Suppression of PITPNM3 abrogates CCL18-induced invasion and metastasis in xenograft models. siRNA knockdown of PITPNM3, intracellular calcium signaling assay, integrin clustering assay, invasion assay, breast cancer xenograft mouse model Cancer Cell High 21481794
2013 CCL18 binding to PITPNM3 (Nir1) promotes phosphorylation of Akt, LIMK, and cofilin (facilitating actin polymerization), and stabilizes Snail via the PI3K/Akt/GSK3β signaling pathway, thereby inducing epithelial-mesenchymal transition (EMT) and breast cancer invasion. LY294002 (PI3K inhibitor) blocked lung metastasis in vivo. Western blot for phosphorylation, siRNA knockdown, in vivo lung metastasis model, PI3K inhibitor (LY294002) treatment European Journal of Cancer Medium 24001613
2015 CCL18 binding to PITPNM3 activates NF-κB signaling (phosphorylation of IKK and IκBα, p65 nuclear translocation) to promote hepatocellular carcinoma cell migration, invasion, and EMT. siRNA silencing of PITPNM3 abolished these effects in PITPNM3-positive HCC cells. siRNA knockdown of PITPNM3, Western blot for IKK/IκBα phosphorylation, p65 nuclear translocation assay, migration/invasion assay Tumour Biology Medium 26449829
2016 CCL18 binding to PITPNM3 (Nir1) in NSCLC cells modulates cytoskeleton reorganization via RAC1 activation in an ELMO1-dependent manner, and enhances cell adhesion by activating ELMO1-integrin β1 signaling. siRNA knockdown, RAC1 activation assay, ELMO1 co-signaling analysis, adhesion assay, invasion assay Molecular Carcinogenesis Medium 26756176
2007 A missense mutation Q626H in the C-terminal PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5), indicating that the interaction between PITPNM3 and PYK2 is important for its function in mammalian phototransduction. Genetic linkage refinement, direct sequencing of PITPNM3 in CORD5 families, mutation mapping to PYK2-interacting domain European Journal of Human Genetics Medium 17377520
2020 CCL18 binding to PITPNM3 (NIR1) in oral squamous cell carcinoma cells activates the JAK2/STAT3 signaling pathway to promote cancer cell growth, metastasis, and EMT. Knockdown of NIR1 or treatment with JAK inhibitor AG490 blocked rCCL18-induced effects. siRNA knockdown of NIR1, Western blot for JAK2/STAT3 phosphorylation, pharmacological inhibition (AG490), proliferation/invasion/migration assays BMC Cancer Medium 32641093
2022 PITPNM3 (Nir1) constitutively localizes at ER-PM junctions and interacts with Nir2 via a region between the FFAT motif and the DDHD domain. Nir1 potentiates Nir2 targeting to ER-PM junctions during receptor-mediated signaling and is required for efficient plasma membrane PIP2 replenishment. Live-cell imaging (constitutive ER-PM junction localization), biochemical co-immunoprecipitation (Nir1-Nir2 interaction), domain-mapping analysis, PIP2 replenishment assay Molecular Biology of the Cell High 35020418
2022 In human microglial cells, CCL18-induced phagocytosis is mediated by CCR8 rather than PITPNM3; selective knockdown of CCR8 (not PITPNM3) blocked CCL18-induced phagocytosis through the NF-κB/Src signaling pathway. PITPNM3 knockdown did not affect microglial phagocytosis. siRNA selective knockdown of CCR8 vs PITPNM3, phagocytosis assay (amyloid-β and dextran uptake), Western blot for NF-κB/Src signaling Journal of Interferon & Cytokine Research Medium 35041514
2020 Mfn-2 suppresses PITPNM3 expression by interacting with transcription factor SP1, thereby reducing SP1 binding to the PITPNM3 promoter. SP1 overexpression increases PITPNM3 mRNA and promotes tumor growth; Mfn-2 overexpression reverses these effects. Co-immunoprecipitation (Mfn-2/SP1 interaction), ChIP assay (SP1 binding to PITPNM3 promoter), RT-PCR for PITPNM3 mRNA, in vivo tumorigenicity assay in nude mice Medical Science Monitor Medium 31955176
2025 The LNS2 domain of PITPNM3 (Nir1) binds phosphatidic acid (PA) and PIP2 in vitro (liposome binding assays), but only PA is necessary and sufficient for membrane localization in cells. This PILS-Nir1 domain functions as a sensitive PA biosensor in live cells. Liposome binding assay, live-cell fluorescence imaging of PILS-Nir1 biosensor, pharmacological and genetic manipulation in HEK293A cells bioRxiv (preprint)preprint Medium 38464273

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer cell 535 21481794
1995 A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13. Genomics 71 8586428
2013 Nir1 promotes invasion of breast cancer cells by binding to chemokine (C-C motif) ligand 18 through the PI3K/Akt/GSK3β/Snail signalling pathway. European journal of cancer (Oxford, England : 1990) 61 24001613
2015 CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 58 26449829
2007 Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families. European journal of human genetics : EJHG 50 17377520
2016 CC chemokine ligand 18(CCL18) promotes migration and invasion of lung cancer cells by binding to Nir1 through Nir1-ELMO1/DOC180 signaling pathway. Molecular carcinogenesis 45 26756176
2020 CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway. BMC cancer 31 32641093
2003 Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance. Human mutation 31 12552567
1993 nir1, a conditional-lethal mutation in barley causing a defect in nitrite reduction. Molecular & general genetics : MGG 21 8437574
2022 Nir1 constitutively localizes at ER-PM junctions and promotes Nir2 recruitment for PIP2 homeostasis. Molecular biology of the cell 19 35020418
2016 Transforming Growth Factor Beta-Induced Factor 2-Linked X (TGIF2LX) Regulates Two Morphogenesis Genes, Nir1 and Nir2 in Human Colorectal. Acta medica Iranica 17 27309477
2010 PITPNM3 is an uncommon cause of cone and cone-rod dystrophies. Ophthalmic genetics 14 20590364
2006 A defect in nir1, a nirA-like transcription factor, confers morphological abnormalities and loss of pathogenicity in Colletotrichum acutatum. Molecular plant pathology 14 20507451
2022 Small Molecular Inhibitors Reverse Cancer Metastasis by Blockading Oncogenic PITPNM3. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 36285700
2012 Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation. Acta ophthalmologica 8 22405330
2020 Mitofusin-2 (Mfn-2) Might Have Anti-Cancer Effect through Interaction with Transcriptional Factor SP1 and Consequent Regulation on Phosphatidylinositol Transfer Protein 3 (PITPNM3) Expression. Medical science monitor : international medical journal of experimental and clinical research 6 31955176
2018 AUTOIMMUNE RETINOPATHY IN A PATIENT WITH A MISSENSE MUTATION IN PITPNM3. Retinal cases & brief reports 5 29176531
2024 Long non-coding RNA MIR600HG as a ceRNA inhibits the pancreatic cancer progression through regulating the miR-1197/PITPNM3 axis. Heliyon 4 38312687
2022 Chemokine CCL18 Promotes Phagocytosis Through Its Receptor CCR8 Rather than PITPNM3 in Human Microglial Cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 4 35041514
1995 The Nir1 locus in barley is tightly linked to the nitrite reductase apoprotein gene Nii. Molecular & general genetics : MGG 4 7603437
2025 Evidence of SUFBC2D directly deliver Fe-S cluster to apo- NITRITE REDUCTASE1 (NIR1). Biochemical and biophysical research communications 1 40081235
2025 Generating a Preclinical Model for PITPNM3 and Evaluating Genotype-Phenotype Concordance: Insights from a Mouse Model. Cells 1 41148841
2024 MIP-4 is Induced by Bleomycin and Stimulates Cell Migration Partially via Nir-1 Receptor. Biochemistry research international 1 39132322
2025 PILS-Nir1 is a novel phosphatidic acid biosensor that reveals mechanisms of lipid production. bioRxiv : the preprint server for biology 0 38464273

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