Affinage

TSPAN5

Tetraspanin-5 · UniProt P62079

Length
268 aa
Mass
30.3 kDa
Annotated
2026-06-10
20 papers in source corpus 10 papers cited in narrative 10 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

TSPAN5 is a TspanC8 tetraspanin that functions as a partner and trafficking chaperone for the metalloprotease ADAM10, controlling where and on which substrates ADAM10 acts (PMID:28428248). It binds ADAM10 directly through two TspanC8-specific motifs in its large extracellular loop, governs ADAM10 exit from the endoplasmic reticulum, and thereby determines ADAM10 substrate cleavage and downstream Notch signaling (PMID:28428248). Through this axis, TSPAN5 promotes ADAM10 maturation and increased γ-secretase–dependent Notch1 cleavage, driving EMT and actin cytoskeleton rearrangement in hepatocellular carcinoma (PMID:33955149) and activating Notch-1/Jagged-1 signaling to promote trophoblast cell fusion (PMID:37485669); closely related TSPAN5 and TSPAN17 control ADAM10-mediated VE-cadherin cleavage in endothelial cells to support T lymphocyte transmigration under flow (PMID:28600292). Independently of its ADAM10 role, TSPAN5 promotes exocytosis of AMPA receptors in hippocampal neurons by interacting with the AP4 adaptor complex and Stargazin, plausibly via recycling endosomes (PMID:36795458), and it regulates serotonin pathway gene expression and media serotonin levels in neuronal cells (PMID:26903268). TSPAN5 also supports RANKL-induced osteoclast cell fusion (PMID:17965585) and, via effects on actin polymerization and the MRTF-A–FLNA complex, restrains oncogene-induced senescence (PMID:34771537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2007 Medium

    Established the first functional role for TSPAN5 by linking it to cell-cell fusion, before any molecular mechanism was known.

    Evidence Expression profiling and siRNA knockdown during RANKL-induced osteoclastogenesis in RAW264.7 cells

    PMID:17965585

    Open questions at the time
    • No molecular partner or pathway identified
    • Mechanism connecting TSPAN5 to fusion machinery unknown
  2. 2016 Medium

    Connected TSPAN5 to neurotransmitter metabolism, showing it influences serotonin biosynthesis gene expression and serotonin output.

    Evidence siRNA knockdown and cDNA overexpression in a neuroblastoma cell line with qRT-PCR and serotonin metabolite measurement

    PMID:26903268

    Open questions at the time
    • Mechanism by which TSPAN5 controls TPH1/TPH2/DDC/MAOA expression unknown
    • No direct molecular interaction defined
  3. 2017 High

    Defined the core molecular function of TSPAN5 as a direct ADAM10 partner that controls ADAM10 ER exit and substrate-selective cleavage including Notch activation.

    Evidence Reciprocal Co-IP in human cell lines and mouse tissues, mutagenesis of TspanC8-specific extracellular motifs, and Notch reporter assays

    PMID:28428248

    Open questions at the time
    • Structural basis of the TSPAN5–ADAM10 interface not resolved
    • How substrate selectivity is encoded not fully defined
  4. 2017 High

    Extended the TSPAN5–ADAM10 axis to endothelial biology, showing TSPAN5 (with TSPAN17) controls VE-cadherin cleavage and enables T cell transmigration.

    Evidence siRNA knockdown of individual TspanC8s in primary HUVECs with in vitro flow-based transmigration assays and VE-cadherin measurement

    PMID:28600292

    Open questions at the time
    • In vivo relevance to immune trafficking not established
    • Redundancy with TSPAN17 not fully dissected
  5. 2020 Medium

    Broadened the TSPAN5 interactome to vesicular trafficking machinery and tied its expression to interferon signaling and alcohol-responsive metabolite changes.

    Evidence Co-IP/mass spectrometry for physical interactors and iPSC-derived neurons/astrocytes with gene expression and metabolite profiling

    PMID:32753686

    Open questions at the time
    • Functional consequence of clathrin interaction not tested
    • Causal link between TSPAN5 and interferon gene changes unresolved
  6. 2021 Medium

    Showed TSPAN5 drives cancer metastasis through ADAM10 maturation and Notch1 cleavage, and separately restrains senescence via actin/MRTF-A-FLNA signaling.

    Evidence Gain- and loss-of-function in HCC cells with migration, metastasis, senescence, and Co-IP assays in vitro and in vivo

    PMID:33955149 PMID:34771537

    Open questions at the time
    • Whether the senescence (actin/MRTF) and Notch arms are mechanistically linked unclear
    • Direct ADAM10-independence of the MRTF-A-FLNA effect not established
  7. 2023 High

    Identified an ADAM10-independent neuronal function: TSPAN5 promotes AMPA receptor exocytosis through AP4 and Stargazin.

    Evidence Surface trafficking and live-cell imaging in rat hippocampal neurons with reciprocal Co-IP for AP4 and Stargazin and KD/OE experiments

    PMID:36795458

    Open questions at the time
    • Whether recycling endosomes are the obligate route not proven
    • Relationship to TSPAN5's ADAM10 role not addressed
  8. 2023 Medium

    Confirmed TSPAN5 drives cell fusion in a second system, trophoblast syncytialization, through Notch-dependent EMT.

    Evidence siRNA knockdown/overexpression in FSK-treated BeWo cells with DAPT (γ-secretase) rescue and fusion/EMT marker readouts

    PMID:37485669

    Open questions at the time
    • Direct ADAM10 involvement in trophoblast fusion not shown
    • In vivo placental relevance untested
  9. 2026 Low

    Placed TSPAN5 downstream of a transcriptional regulator, with Claudin11 controlling TSPAN5 expression and Notch activity in osteoarthritis.

    Evidence Cldn11-RNAi lentivirus in a rat OA model with pathway readouts and Notch inhibitor treatment

    PMID:41485015

    Open questions at the time
    • Cldn11–Tspan5 transcriptional link not mechanistically dissected
    • Single lab, single publication
    • Whether regulation is direct or indirect unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TSPAN5's ADAM10-dependent metalloprotease scaffolding role mechanistically relates to its ADAM10-independent neuronal trafficking and serotonin-regulatory functions remains unresolved.
  • No unified model linking ADAM10 trafficking, AMPAR exocytosis, and serotonin metabolism
  • No structural model of TSPAN5 complexes
  • Tissue-specific partner switching not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-392499 Metabolism of proteins 1
Partners
ADAM10AP4CLATHRINFLNAMRTF-ASTARGAZIN

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 TSPAN5 directly interacts with ADAM10 (a disintegrin and metalloproteinase 10), regulates ADAM10 exit from the endoplasmic reticulum and its subsequent trafficking, and differentially regulates ADAM10's ability to cleave substrates and activate Notch signaling. Two TspanC8-specific motifs in the large extracellular domain of Tspan5 are important for ADAM10 interaction and ER exit. The fraction of Tspan5 not associated with ADAM10 is minor in tested cell lines. Co-immunoprecipitation with novel monoclonal antibodies in human cell lines and mouse tissues; mutagenesis of TspanC8-specific motifs; Notch signaling reporter assays; antibody inhibition experiments The Journal of biological chemistry High 28428248
2017 Tspan5 and Tspan17 (the two most closely related TspanC8 tetraspanins) are the only TspanC8 members that regulate VE-cadherin expression on endothelial cells and are required for T lymphocyte transmigration under flow. Tspan5-ADAM10 complexes maintain normal VE-cadherin expression by controlling ADAM10-mediated proteolytic cleavage, thereby promoting T lymphocyte transmigration. siRNA knockdown of individual TspanC8s in primary HUVECs; in vitro flow-based transmigration assay with freshly isolated human peripheral blood T lymphocytes; VE-cadherin expression measurement Journal of immunology (Baltimore, Md. : 1950) High 28600292
2007 Tspan5 expression is upregulated during RANKL-induced osteoclastogenesis in RAW264.7 cells, and siRNA-mediated knockdown of Tspan5 suppresses RANKL-induced cell fusion during osteoclastogenesis, indicating a positive regulatory role in polykaryon formation. RT-PCR and quantitative real-time RT-PCR for expression profiling; gene-specific siRNA knockdown in RAW264.7 cells; assessment of cell fusion during RANKL-stimulated osteoclastogenesis Allergology international : official journal of the Japanese Society of Allergology Medium 17965585
2021 Tspan5 promotes tumor metastasis of hepatocellular carcinoma (HCC) by increasing the enzymatic maturation of ADAM10 and activating Notch signaling through increased cleavage of the Notch1 receptor catalyzed by the γ-secretase complex, leading to enhanced EMT and actin cytoskeleton rearrangement. Lentiviral overexpression and knockdown of Tspan5 in HCC cells; wound healing and migration assays in vitro; tumor metastasis assay in vivo; western blot for ADAM10 maturation and Notch pathway components; correlation analysis in clinical HCC samples Molecular oncology Medium 33955149
2021 Depletion of TSPAN5 in HCC cells induces oncogene-induced senescence (OIS) mediated by the p16INK4a/pRb pathway. Mechanistically, TSPAN5 silencing reduces actin polymerization and thereby disrupts myocardin-related transcription factor A–filamin A (MRTF-A–FLNA) complex formation, resulting in decreased expression of MRTF/SRF-dependent target genes and senescence induction both in vitro and in vivo. siRNA/shRNA knockdown of TSPAN5 in HCC cell lines; senescence assays (SA-β-gal, p16INK4a/pRb pathway markers); actin polymerization assays; co-immunoprecipitation for MRTF-A–FLNA complex; in vivo tumor xenograft experiments Cancers Medium 34771537
2023 In rat hippocampal neurons, TSPAN5 promotes exocytosis of AMPA receptors without affecting their internalization. TSPAN5 mediates this function by interacting with the adaptor protein complex AP4 and Stargazin, and possibly uses recycling endosomes as a delivery route. Live-cell imaging and surface receptor trafficking assays in rat hippocampal neurons; co-immunoprecipitation for AP4 complex and Stargazin; knockdown and overexpression experiments with defined AMPAR exocytosis readout eLife High 36795458
2016 Knockdown and overexpression of TSPAN5 in a neuroblastoma cell line significantly altered expression of serotonin pathway genes (TPH1, TPH2, DDC, and MAOA) and changed media serotonin concentrations, indicating a functional role for TSPAN5 in regulating serotonin biosynthesis/metabolism. siRNA knockdown and cDNA overexpression in neuroblastoma cell line; qRT-PCR for serotonin pathway gene expression; measurement of media serotonin concentrations Molecular psychiatry Medium 26903268
2020 TSPAN5 physically interacts with clathrin and other vesicle-related proteins (identified by co-immunoprecipitation/proteomics), suggesting a role in vesicular function. Knockdown of TSPAN5 also influenced expression of genes associated with interferon signaling pathways, and ethanol or acamprosate treatment downregulated TSPAN5 expression alongside decreased serotonin and kynurenine concentrations in iPSC-derived neurons and astrocytes. Co-immunoprecipitation/mass spectrometry for TSPAN5 physical interactors; iPSC-derived neurons and astrocytes; gene expression profiling; metabolite measurement Molecular psychiatry Medium 32753686
2023 Tspan5 promotes trophoblast cell fusion (syncytialization) by activating the Notch pathway (upregulating Notch-1 and Jagged-1), which in turn activates the EMT process. Knockdown of Tspan5 inhibited cell fusion and EMT-related protein levels in FSK-treated BeWo cells; blocking the Notch pathway with DAPT reversed these effects. siRNA knockdown and overexpression of Tspan5 in BeWo cells; FSK-induced syncytialization model; immunofluorescence for cell fusion; western blot and qRT-PCR for fusion and EMT markers; DAPT (γ-secretase/Notch inhibitor) rescue experiment Zygote (Cambridge, England) Medium 37485669
2026 Claudin11 (Cldn11) transcriptionally regulates Tspan5 expression; knockdown of Cldn11 suppresses Tspan5 expression and downstream Notch signaling pathway activity in a Tspan5-dependent manner, accelerating cartilage degeneration in an osteoarthritis model. Cldn11-RNAi lentivirus injection in rat OA model; qRT-PCR, western blot, and immunohistochemistry for Tspan5 and Notch pathway components; Notch pathway inhibitor treatment; mechanical pain threshold assessment Journal of orthopaedic surgery and research Low 41485015

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics. Molecular psychiatry 101 26903268
2020 miR-155 increases stemness and decitabine resistance in triple-negative breast cancer cells by inhibiting TSPAN5. Molecular carcinogenesis 44 32096299
2017 ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin Expression and Promote T Lymphocyte Transmigration. Journal of immunology (Baltimore, Md. : 1950) 44 28600292
2007 Expression and function of transmembrane-4 superfamily (tetraspanin) proteins in osteoclasts: reciprocal roles of Tspan-5 and NET-6 during osteoclastogenesis. Allergology international : official journal of the Japanese Society of Allergology 35 17965585
2021 Tspan5 promotes epithelial-mesenchymal transition and tumour metastasis of hepatocellular carcinoma by activating Notch signalling. Molecular oncology 30 33955149
2017 New insights into the tetraspanin Tspan5 using novel monoclonal antibodies. The Journal of biological chemistry 27 28428248
2001 Pattern of expression of the tetraspanin Tspan-5 during brain development in the mouse. Mechanisms of development 24 11472858
2020 TSPAN5 influences serotonin and kynurenine: pharmacogenomic mechanisms related to alcohol use disorder and acamprosate treatment response. Molecular psychiatry 22 32753686
2000 Mouse Tspan-5, a member of the tetraspanin superfamily, is highly expressed in brain cortical structures. Neuroreport 21 11043545
2005 Tetraspanin-5 (Tm4sf9) mRNA expression parallels neuronal maturation in the cerebellum of normal and L7En-2 transgenic mice. The Journal of comparative neurology 18 15682397
2021 Tetraspanin 5 (TSPAN5), a Novel Gatekeeper of the Tumor Suppressor DLC1 and Myocardin-Related Transcription Factors (MRTFs), Controls HCC Growth and Senescence. Cancers 16 34771537
2012 Expression of the tetraspanin family members Tspan3, Tspan4, Tspan5 and Tspan7 during Xenopus laevis embryonic development. Gene expression patterns : GEP 14 22940433
2018 The increased level of Tspan5 in villi suggests more proliferation and invasiveness of trophoblasts in tubal pregnancy. European journal of obstetrics, gynecology, and reproductive biology 11 29908376
2022 MiR-322-5p Alleviates Cell Injury and Impairment of Cognitive Function in Vascular Dementia by Targeting TSPAN5. Yonsei medical journal 9 35184431
2017 Is the tungsten(IV) complex (NEt4)2[WO(mnt)2] a functional analogue of acetylene hydratase? Beilstein journal of organic chemistry 9 29181113
1996 Magnetochemical Properties and Reactions of Vanadium(III) Thiolate Complexes: Preparation of (NEt(4))(3)[V(3)Cl(6)(edt)(3)] and Mixed-Valence (NEt(4))[V(2)(edt)(4)] (edt = Ethane-1,2-dithiolate). Inorganic chemistry 8 11666852
2023 The tetraspanin TSPAN5 regulates AMPAR exocytosis by interacting with the AP4 complex. eLife 6 36795458
2023 Tspan5 promotes the EMT process to regulate the syncytialization of trophoblast cells by activating Notch signalling. Zygote (Cambridge, England) 2 37485669
2008 [Expression of TM4SF9 in human trophoblasts]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 18583270
2026 Cldn11 deficiency aggravates osteoarthritis by inhibiting Notch signalling in a Tspan5-dependent manner. Journal of orthopaedic surgery and research 0 41485015

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