Affinage

TCAF2

TRPM8 channel-associated factor 2 · UniProt A6NFQ2

Length
919 aa
Mass
100.9 kDa
Annotated
2026-06-10
12 papers in source corpus 5 papers cited in narrative 5 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

TCAF2 is a TRPM8 channel-associated factor that governs cell migration and invasion across multiple cancer contexts by coupling regulation of TRPM8 to downstream STAT3 signaling (PMID:25559186, PMID:37635201). It physically binds the TRPM8 channel and promotes its trafficking to the cell surface while potentiating its gating activity, in contrast to its paralog TCAF1, which reduces channel activity; functionally, TCAF2 promotes migration of prostate cancer cells (PMID:25559186). In tumor pericytes, TCAF2 inhibits TRPM8 expression and activity, driving Wnt5a secretion that activates STAT3 in adjacent tumor cells to promote epithelial-mesenchymal transition and colorectal cancer liver metastasis, a phenotype attenuated by pericyte-specific Tcaf2 knockout and by the TRPM8 agonist menthol (PMID:37635201). The pro-migratory, EMT-promoting role of TCAF2 via JAK2/STAT3 activation extends to glioma (PMID:38019450) and to gastric cancer, where TCAF2 acts as a required intermediate downstream of PDE12 (PMID:40628363). Context-dependence is evident, as TCAF2 inhibition instead promotes migration and invasion in pancreatic ductal adenocarcinoma, indicating a motility-restraining role in that setting (PMID:32127956).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2015 High

    Established that TCAF2 is a physical partner and trafficking/gating regulator of the TRPM8 channel, distinguishing it functionally from its paralog TCAF1 and linking it to cancer cell migration.

    Evidence Reciprocal Co-IP, cell surface trafficking assays, electrophysiology, and migration assays with loss-/gain-of-function in prostate cancer cells

    PMID:25559186

    Open questions at the time
    • Molecular basis for the opposing gating effects of TCAF2 versus TCAF1 not resolved
    • Signaling pathway linking TRPM8 modulation to migration not defined in this study
  2. 2023 High

    Connected TCAF2 to a paracrine metastatic mechanism, showing it suppresses TRPM8 to drive pericyte Wnt5a secretion and tumor-cell STAT3-dependent EMT in vivo.

    Evidence Pericyte-conditional Tcaf2-knockout mice, proteomics, TRPM8 activity and Wnt5a secretion assays, STAT3 phosphorylation western blot, in vivo metastasis models with menthol rescue

    PMID:37635201

    Open questions at the time
    • Mechanism by which TCAF2 inhibits TRPM8 expression not defined
    • How TRPM8 activity controls Wnt5a secretion mechanistically unresolved
  3. 2023 Medium

    Extended the TCAF2-STAT3-EMT axis to glioma, supporting a generalizable pro-migratory function across tumor types.

    Evidence Transwell/scratch assays, EMT marker and STAT3 western blots, gain-/loss-of-function in glioma lines, IHC on tissue microarray

    PMID:38019450

    Open questions at the time
    • No in vivo validation
    • TRPM8 involvement in glioma not tested
    • Single lab
  4. 2025 Medium

    Placed TCAF2 as a required intermediate in a PDE12/JAK2/STAT3 oncogenic axis in gastric cancer via epistasis.

    Evidence PDE12 and TCAF2 overexpression/knockdown with rescue, JAK2/STAT3 and EMT marker western blots, proliferation/migration/invasion and cell cycle assays

    PMID:40628363

    Open questions at the time
    • Mechanism by which PDE12 regulates TCAF2 expression unknown
    • No in vivo validation
    • Direct biochemical link of TCAF2 to JAK2 not established
  5. 2020 Medium

    Revealed context-dependent function, with TCAF2 inhibition promoting rather than restraining migration in pancreatic cancer.

    Evidence siRNA knockdown, migration/invasion and proliferation assays, IHC for subcellular localization in PDAC cells

    PMID:32127956

    Open questions at the time
    • Mechanistic pathway not defined
    • Reason for opposite directionality versus other cancers unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TCAF2 reconciles its dual context-dependent roles—promoting versus restraining migration—and the molecular basis of its TRPM8-independent signaling remain unresolved.
  • No unifying mechanism explaining tissue-specific opposite phenotypes
  • Direct biochemical link between TCAF2 and JAK2/STAT3 not established
  • No structural model of TCAF2-TRPM8 interaction

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2
Partners
TRPM8

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TCAF2 physically binds to the TRPM8 channel and promotes its trafficking to the cell surface, while exerting opposing effects on TRPM8 gating properties compared to TCAF1 (TCAF1 reduces channel activity; TCAF2 promotes it). TCAF2 also promotes migration of prostate cancer cells, in contrast to TCAF1 which reduces migration speed and directionality. Co-immunoprecipitation (binding), cell surface trafficking assays, electrophysiology (gating), and cell migration assays (Transwell/scratch); loss- and gain-of-function experiments in prostate cancer cells The Journal of cell biology High 25559186
2023 In tumor pericytes, TCAF2 inhibits the expression and activity of TRPM8, leading to Wnt5a secretion from pericytes, which in turn activates the STAT3 signaling pathway in tumor cells to facilitate epithelial-mesenchymal transition (EMT) and colorectal cancer liver metastasis. Pericyte-conditional Tcaf2 knockout in mice attenuates metastasis, and the TRPM8 agonist menthol suppresses Wnt5a secretion and metastasis. Gain- and loss-of-function experiments in pericytes, pericyte-conditional Tcaf2-knockout mice, proteomic analysis, TRPM8 activity assays, Wnt5a secretion measurement, STAT3 phosphorylation western blot, in vivo metastasis models Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 37635201
2023 Elevated TCAF2 expression promotes glioma cell migration and invasion through an EMT-like process mediated by activation of the STAT3 signaling pathway. Transwell and scratch assays for migration/invasion, western blotting for EMT markers and STAT3 phosphorylation, gain- and loss-of-function in glioma cell lines, immunohistochemistry on glioma tissue microarray Molecular and cellular biochemistry Medium 38019450
2025 PDE12 positively regulates TCAF2 expression in gastric cancer cells, and TCAF2 functions downstream of PDE12 to promote gastric cancer cell proliferation, migration, invasion, and EMT via activation of the JAK2/STAT3 signaling pathway. TCAF2 knockdown reverses the pro-tumorigenic effects of PDE12 overexpression, placing TCAF2 as a required intermediate in the PDE12/JAK2/STAT3 axis. Gain- and loss-of-function experiments (overexpression and knockdown of PDE12 and TCAF2), western blotting for JAK2/STAT3 phosphorylation and EMT markers, proliferation and migration/invasion assays, cell cycle analysis Biochimica et biophysica acta. Molecular basis of disease Medium 40628363
2020 FAM115C (TCAF2) inhibition promotes pancreatic ductal adenocarcinoma (PDAC) cell migration and invasion in vitro without affecting proliferation, suggesting a tumor-suppressive role in restraining cell motility in PDAC. Protein was localized mainly to the nucleus but also the cytoplasm in PDAC cells. siRNA-mediated knockdown of FAM115C/TCAF2, migration and invasion assays, proliferation assay, immunohistochemistry for subcellular localization Journal of Cancer Medium 32127956

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 TRP channel-associated factors are a novel protein family that regulates TRPM8 trafficking and activity. The Journal of cell biology 83 25559186
2023 TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 37635201
2021 Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans. Nature communications 17 34433829
2017 LncRNA Expression in CD4+ T Cells in Neurosyphilis Patients. Frontiers in cellular and infection microbiology 12 29167762
2020 FAM115C could be a novel tumor suppressor associated with prolonged survival in pancreatic cancer patients. Journal of Cancer 10 32127956
2022 The Association between TRP Channels Expression and Clinicopathological Characteristics of Patients with Pancreatic Adenocarcinoma. International journal of molecular sciences 9 36012311
2019 Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice. International journal of molecular sciences 7 31151297
2022 Hypoxia classifier for transcriptome datasets. BMC bioinformatics 6 35641902
2024 Key Genes Involved in the Beneficial Mechanism of Hyperbaric Oxygen for Glioblastoma and Predictive Indicators of Hyperbaric Oxygen Prolonging Survival in Glioblastoma Patients. Current medical science 5 39446287
2023 TCAF2 drives glioma cellular migratory/invasion properties through STAT3 signaling. Molecular and cellular biochemistry 3 38019450
2025 Phosphodiesterase 12 facilitates the growth and metastatic capabilities of gastric cancer cells by activating the TCAF2/JAK2/STAT3 axis. Biochimica et biophysica acta. Molecular basis of disease 0 40628363
2024 When is an SNP not an SNP? BioTechniques 0 39263936

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