Affinage

STAM2

Signal transducing adapter molecule 2 · UniProt O75886

Length
525 aa
Mass
58.2 kDa
Annotated
2026-06-10
22 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAM2 is an ESCRT-0 adaptor that recognizes ubiquitinated cargo on early endosomes and couples it to deubiquitination and lysosomal sorting machinery (PMID:21121635, PMID:27725184). Cargo recognition is achieved through cooperative use of three ubiquitin-binding modules: the VHS and UIM domains together bind K63-linked polyubiquitin with avidity not seen for monoubiquitin or K48 chains, with the distal ubiquitin stabilizing UIM helix formation, and the SH3 domain providing a third ubiquitin-binding site, explaining the selectivity for K63-polyubiquitinated cargo destined for degradation (PMID:21121635, PMID:22493438, PMID:22841719). Interdomain linker length and flexibility between UIM and SH3 tune this K63-diubiquitin recognition (PMID:31601934). The SH3 domain doubles as a deubiquitinase-recruitment surface: an AMSH-derived motif outcompetes K63-diubiquitin for SH3 binding and positions AMSH for chain cleavage, while a UBPY-derived peptide likewise competes for the same site (PMID:22841719, PMID:27725184). STAM2 engages downstream sorting machinery through a defined interface with the HD-PTP Bro1 domain, where Thr145 of HD-PTP discriminates it from Alix/Brox (PMID:26866605). STAM2 is tyrosine-phosphorylated by JAK1/JAK2 in a manner requiring its ITAM domain and is dephosphorylated by PTP1B; phosphorylation state controls endosomal dwell time and Akt output, with phosphorylation-deficient STAM2 showing prolonged endosomal localization and suppressed Akt activation (PMID:10993906, PMID:20504764). In T cells, combined loss of STAM1/STAM2 reduces thymocyte and peripheral T-cell numbers and increases apoptosis, defining a pro-survival role downstream of TCR signaling (PMID:12446783). In cancer contexts STAM2 bridges cell-surface PD-L1 to HRS to drive PD-L1+ extracellular vesicle biogenesis, and O-GlcNAcylation at Ser375 stabilizes STAM2 to promote JAK2/STAT3-driven phenotypes (PMID:40541896, PMID:40075080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2000 Medium

    Established STAM2 as a substrate and partner of JAK kinases, linking it to cytokine and growth factor receptor signaling rather than only endosomal trafficking.

    Evidence Anti-phosphotyrosine purification/MS, kinase co-expression, ITAM deletion mutants and c-Myc reporter assays; reciprocal co-IP with Jak2/Jak3 and SH3 deletion mutants in DNA synthesis assays

    PMID:10899310 PMID:10993906

    Open questions at the time
    • Phosphorylation sites not mapped at this stage
    • Functional consequence of JAK association on trafficking not addressed
    • Relative contribution of STAM1 vs STAM2 unresolved
  2. 2002 High

    Defined an in vivo physiological role for STAMs as pro-survival factors required for T-cell development, distinct from proximal cytokine signaling.

    Evidence Conditional STAM1/STAM2 double knockout with flow cytometry, proliferation, signaling western blots and viability assays

    PMID:12446783

    Open questions at the time
    • STAM2-specific (vs STAM1) contribution not isolated
    • Molecular link between ESCRT function and apoptosis suppression unknown
    • How prolonged p38/JNK activation arises mechanistically not resolved
  3. 2010 Medium

    Identified PTP1B as the phosphatase regulating STAM2 and linked its phosphorylation state to endosomal dwell time and Akt signaling output.

    Evidence Co-IP, PTP1B knockdown, phospho-deficient mutant imaging and Akt activation assays

    PMID:20504764

    Open questions at the time
    • Specific tyrosine sites controlling localization not fully defined
    • Mechanism connecting phospho-state to dwell time unclear
    • Single-lab finding without reciprocal validation
  4. 2012 High

    Provided structural basis for STAM2's selectivity toward K63-linked polyubiquitin, explaining preferential sorting of K63-modified cargo.

    Evidence NMR solution structures with monoubiquitin and diubiquitin variants, ITC affinity measurements with VHS and VHS-UIM constructs

    PMID:21121635 PMID:22493438

    Open questions at the time
    • In vivo cargo specificity not directly tested
    • Length of physiological polyubiquitin chains engaged unknown
    • Contribution of full-length protein context not assessed
  5. 2016 High

    Resolved how STAM2 SH3 doubles as a ubiquitin-binding and DUB-recruitment surface and how it docks onto downstream sorting machinery.

    Evidence NMR structure of AMSH-SBM/SH3 complex with competitive binding and kinetics; crystal structure of HD-PTP Bro1 domain with STAM2 core and Thr145 mutagenesis

    PMID:22841719 PMID:26866605 PMID:27725184

    Open questions at the time
    • Ordering/handoff between ubiquitin binding and DUB recruitment in cells not established
    • Functional consequence of HD-PTP interaction on sorting not measured
    • Competition dynamics in native complexes unquantified
  6. 2019 Medium

    Showed that interdomain dynamics, not just individual domain affinities, tune K63-diubiquitin recognition.

    Evidence SAXS, NMR and engineered UIM-SH3 linker variants with affinity measurements

    PMID:31601934

    Open questions at the time
    • Physiological regulation of linker conformation unknown
    • Whether linker dynamics are modulated in cells unaddressed
  7. 2025 Medium

    Extended STAM2 function to cargo-specific extracellular vesicle biogenesis and PTM-dependent oncogenic signaling.

    Evidence Co-IP/domain mapping for PD-L1-VHS and HRS-ITAM bridging with sEV isolation; MS site mapping of Ser375 O-GlcNAcylation with proteasome and JAK2/STAT3 phosphorylation assays; gastric cancer knockdown with functional and rescue assays

    PMID:33778841 PMID:40075080 PMID:40541896

    Open questions at the time
    • Generality of PD-L1 bridging beyond OSCC not tested
    • Link between O-GlcNAcylation and ESCRT sorting function unclear
    • Direct vs indirect role in JAK2/STAT3 activation not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How STAM2 phosphorylation, O-GlcNAcylation, and its ESCRT-0 sorting activity are integrated into a single regulatory logic governing cargo fate and signaling output remains unresolved.
  • No unified model connecting PTM state to cargo selectivity
  • STAM2-specific in vivo functions separate from STAM1 not defined
  • Structural picture of full ESCRT-0 cargo-loaded complex absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005768 endosome 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-168256 Immune System 1
Partners
AMSHHD-PTPHRSJAK2PD-L1PTP1BUBPY
Complex memberships
ESCRT-0

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 STAM2 is tyrosine-phosphorylated downstream of growth factor receptors (EGF, PDGF) and cytokines (IL-3, IL-2); it is phosphorylated by Jak1 and Jak2 (but not the unrelated Tec kinase Etk), requiring the ITAM domain for JAK-mediated phosphorylation; overexpression of wild-type STAM2 potentiates IL-2-mediated c-Myc promoter activation. Anti-phosphotyrosine affinity purification + mass spectrometry identification; co-expression with kinase constructs; deletion mutant analysis; reporter assay The Journal of biological chemistry Medium 10993906
2000 STAM2 physically associates with Jak2 and Jak3 and is involved in DNA synthesis and c-myc induction signaling downstream of IL-2 and GM-CSF; SH3 domain deletion mutants of STAM1 and STAM2 additively suppress DNA synthesis, indicating compensatory roles. Co-immunoprecipitation; SH3 deletion mutants; DNA synthesis assay; c-myc reporter assay FEBS letters Medium 10899310
2002 T-cell-specific double knockout of STAM1 and STAM2 causes significant reduction in thymocytes and peripheral T cells with defective TCR-stimulated proliferation; double-mutant thymocytes show prolonged p38 MAPK and JNK activation and increased apoptosis, but proximal IL-2/IL-7 signaling (STAT5, ERK, PKB/Akt) is normal, placing STAMs in a pro-survival pathway downstream of TCR that suppresses apoptosis. Conditional double knockout (Cre/loxP); flow cytometry; proliferation assays; western blot for signaling intermediates; cell viability assay Molecular and cellular biology High 12446783
2010 PTP1B directly dephosphorylates STAM2 at defined phosphotyrosine sites; knockdown of PTP1B augments STAM2 phosphorylation; phosphorylated STAM2 suppresses Akt activation, and a phosphorylation-deficient STAM2 mutant shows prolonged endosomal localization after EGF stimulation. Co-immunoprecipitation; PTP1B knockdown; phosphorylation-deficient mutant; subcellular localization by imaging; Akt activation assay The Journal of biological chemistry Medium 20504764
2010 NMR solution structure of the STAM2 VHS domain in complex with monoubiquitin; VHS binds K48-linked diubiquitin in a distinct mode (entering the hydrophobic pocket with differential affinity for each subunit) compared with monoubiquitin or K63-linked diubiquitin (similar binding mode to monoubiquitin), explaining VHS preference for K63 chains. Solution NMR; chemical shift perturbations; spin relaxation; paramagnetic relaxation enhancements Biochemistry High 21121635
2012 STAM2 VHS-UIM cooperatively binds K63-linked diubiquitin with avidity not seen for monoubiquitin or K48-linked diubiquitin; the distal ubiquitin of K63 chains stabilizes UIM helical structure and the complex adopts a specific structural organization, explaining better sorting efficiency for K63-polyubiquitinated cargo. NMR; ITC; binding affinity measurements with VHS-UIM construct and diubiquitin variants The Journal of biological chemistry High 22493438
2012 The SH3 domain of STAM2 constitutes a third ubiquitin-binding domain; UBPY-derived peptide and ubiquitin compete for binding to the STAM2 SH3 domain, suggesting the SH3 domain plays dual roles in ubiquitin-mediated receptor sorting and DUB recruitment. NMR chemical shift perturbation; competitive binding assays FEBS letters Medium 22841719
2015 STAM2 localizes to early endosomes in neurons; uniquely, STAM2 also localizes to the nucleus in neurons, distinct from other ESCRT-0 members (Hrs) which co-localize with STAM2 only in the cytoplasm. Subcellular fractionation; co-immunofluorescence confocal microscopy; lacZ reporter gene trap mouse line Molecular and cellular neurosciences Medium 26101075
2016 Crystal structure of the HD-PTP Bro1 domain in complex with the STAM2 core region shows STAM2 binds the hydrophobic concave pocket of HD-PTP Bro1 in the opposite orientation to CHMP4B; Thr145 of HD-PTP is the key determinant distinguishing HD-PTP from Alix/Brox, as Alix- or Brox-mimicking mutations of this residue abolish STAM2 binding. X-ray crystal structure; mutagenesis; binding assays PloS one High 26866605
2016 The AMSH SH3 binding motif (AMSH-SBM) outcompetes Lys63-linked diubiquitin for binding to the STAM2 SH3 domain; NMR structure of AMSH-SBM/SH3 complex reveals structural organization where AMSH-SBM correctly positions AMSH for polyubiquitin chain cleavage, explaining how STAM2 stimulates AMSH deubiquitinase activity. NMR; solution NMR structure; competitive binding assays with kinetic analysis Journal of molecular biology High 27725184
2019 Linker length and flexibility between the UIM and SH3 domains of STAM2 modulates recognition of Lys63-linked diubiquitin; shortening or lengthening the linker reduces affinity for Lys63-Ub2 up to ~8-fold, indicating interdomain dynamics tune binding. SAXS; NMR; engineered linker variants with affinity measurements Scientific reports Medium 31601934
2021 STAM2 knockdown in gastric cancer cells inhibits proliferation, cell cycle progression, migration, and invasion, and decreases phosphorylation of JAK2 and STAT3 as well as expression of MMP2 and MMP9, placing STAM2 upstream of the JAK2/STAT3 signaling axis. siRNA knockdown; CCK-8, EdU, flow cytometry, wound-healing, Boyden chamber assays; western blot; rescue assays Acta biochimica et biophysica Sinica Medium 33778841
2025 STAM2 (not STAM1) directly binds cell-surface PD-L1 via its VHS domain and binds HRS via its ITAM domain, acting as a molecular bridge to initiate biogenesis of PD-L1+ small extracellular vesicles in oral squamous cell carcinoma. Co-immunoprecipitation; domain deletion/mutant analysis; sEV isolation and characterization International journal of biological macromolecules Medium 40541896
2025 O-GlcNAcylation of STAM2 at serine 375 (driven by GFAT1 upregulation) stabilizes STAM2 protein by inhibiting proteasomal degradation and ubiquitination; O-GlcNAcylated STAM2 promotes JAK2 and STAT3 phosphorylation to activate epithelial-mesenchymal transition in bladder cancer. GFAT1 inhibition; OGT inhibitor; mass spectrometry identification of modification site; proteasome assay; western blot for STAT3/JAK2 phosphorylation; metastasis assays Scientific reports Medium 40075080

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Identification of a novel immunoreceptor tyrosine-based activation motif-containing molecule, STAM2, by mass spectrometry and its involvement in growth factor and cytokine receptor signaling pathways. The Journal of biological chemistry 97 10993906
2000 STAM2, a new member of the STAM family, binding to the Janus kinases. FEBS letters 65 10899310
2002 Signal-transducing adaptor molecules STAM1 and STAM2 are required for T-cell development and survival. Molecular and cellular biology 51 12446783
2010 PTP1B targets the endosomal sorting machinery: dephosphorylation of regulatory sites on the endosomal sorting complex required for transport component STAM2. The Journal of biological chemistry 41 20504764
2012 Evidence for cooperative and domain-specific binding of the signal transducing adaptor molecule 2 (STAM2) to Lys63-linked diubiquitin. The Journal of biological chemistry 20 22493438
2016 Structural Study of the HD-PTP Bro1 Domain in a Complex with the Core Region of STAM2, a Subunit of ESCRT-0. PloS one 18 26866605
2021 STAM2 knockdown inhibits proliferation, migration, and invasion by affecting the JAK2/STAT3 signaling pathway in gastric cancer. Acta biochimica et biophysica Sinica 16 33778841
2012 Competitive binding of UBPY and ubiquitin to the STAM2 SH3 domain revealed by NMR. FEBS letters 12 22841719
2010 NMR reveals a different mode of binding of the Stam2 VHS domain to ubiquitin and diubiquitin. Biochemistry 12 21121635
2015 STAM2, a member of the endosome-associated complex ESCRT-0 is highly expressed in neurons. Molecular and cellular neurosciences 10 26101075
2016 NMR Reveals the Interplay among the AMSH SH3 Binding Motif, STAM2, and Lys63-Linked Diubiquitin. Journal of molecular biology 6 27725184
2006 Splice variant of mouse Stam2 mRNA in nervous and muscle tissue contains additional exon with stop codon within region coding for VHS domain. Croatian medical journal 6 16489693
2011 Neurons and a subset of interstitial cells of Cajal in the enteric nervous system highly express Stam2 gene. Anatomical record (Hoboken, N.J. : 2007) 5 22140097
2019 Molecular recognition of ubiquitin and Lys63-linked diubiquitin by STAM2 UIM-SH3 dual domain: the effect of its linker length and flexibility. Scientific reports 4 31601934
2008 Expression pattern and functional analysis of mouse Stam2 in the olfactory system. Collegium antropologicum 4 18405059
2013 Molecular cloning, polymorphisms, and association analysis of the promoter region of the STAM2 gene in Wuchuan Black cattle. Genetics and molecular research : GMR 3 24085429
2011 Stam2 expression pattern during embryo development. Gene expression patterns : GEP 3 22143071
2025 STAM2-mediated fine-tuning of PD-L1 secretion via small extracellular vesicles in oral squamous cell carcinoma. International journal of biological macromolecules 2 40541896
2024 STAM2 negatively regulates the MyD88-mediated NF-κB signaling pathway in miiuy croaker, Miichthys miiuy. Fish & shellfish immunology 2 38593891
2024 GRASLND regulates melanoma cell progression by targeting the miR-218-5p/STAM2 axis. Journal of translational medicine 2 39060946
2014 Immunohistochemical expression of STAM2 in gastrointestinal stromal tumors. Anticancer research 2 24778033
2025 Starvation-induced HBP metabolic reprogramming and STAM2 O-GlcNAcylation facilitate bladder cancer metastasis. Scientific reports 1 40075080

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