Affinage

SKAP2

Src kinase-associated phosphoprotein 2 · UniProt O75563

Length
359 aa
Mass
41.2 kDa
Annotated
2026-06-10
83 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SKAP2 is a ubiquitously expressed dimeric adaptor protein that couples membrane-proximal kinase signaling to integrin activation and actin cytoskeletal remodeling across myeloid, lymphoid, and developing cells (PMID:22976304, PMID:28183734). Structurally, it is a homodimer in which an N-terminal four-helix bundle dimerization domain packs two PH domains in an autoinhibited conformation incompatible with phosphoinositide binding; PI3K-generated PI[3,4,5]P3 relieves this autoinhibition, driving membrane recruitment and cytoskeletal function, with mutations in either the dimerization domain or the PH binding pocket abolishing localization to membrane ruffles (PMID:19026786). SKAP2 is a substrate of Src-family kinases, associating with Fyn, Hck, and Lyn through Fyn-SH2 recognition, and its phosphorylation at a key tyrosine is required both for Fyn association and for growth-inhibitory activity in myeloid progenitors (PMID:9755858, PMID:9837776, PMID:11063873); its modular dimerization, SH3, and interdomain regions tune Src-family kinase binding, and it is dephosphorylated by the lymphoid phosphatase Lyp (PMID:21719704, PMID:36423812). At engaged integrins, SKAP2 is recruited via Sirpα and orchestrates actin polymerization, podosome formation, β2-integrin activation, and integrin clustering by interacting through its SH3 domain with WASP and by regulating talin-1 and kindlin-3 loading onto the β2 cytoplasmic tail, with loss producing impaired adhesion-coupled responses and a LAD-like phenotype in mice (PMID:22976304, PMID:26577701, PMID:28183734, PMID:38487529). SKAP2 also negatively regulates actin dynamics by binding WAVE2 and cortactin and suppressing their cooperative actin polymerization (PMID:23161539). Genetically, SKAP2 is required for B-cell, dendritic-cell, neutrophil, and monocyte integrin-dependent adhesion and immune function, and for neutrophil/monocyte ROS production against bacterial and fungal pathogens through a SFK–Syk–Pyk2 module (PMID:16135797, PMID:19369640, PMID:28183734, PMID:32352382, PMID:34386732). Beyond immune cells, SKAP2 inhibits TLR4–NF-κB signaling by recruiting a Sirpα/SHP-1 complex to TLR4 adaptors (PMID:35034964), protects β-cells from cytokine-induced apoptosis via the NF-κB–iNOS–ER stress (CHOP) pathway (PMID:33203694), and is required for sperm cytoskeletal integrity and mitochondrial organization downstream of an hnRNPR-controlled m6A splicing axis (PMID:41436426). A de novo gain-of-function PH-domain variant (p.Gly153Arg) produces constitutive integrin activity and migration, and homozygous knockout is embryonic lethal in mice (PMID:34172489, PMID:24846415).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 Medium

    Established SKAP2 as a Src-family-kinase-associated adaptor distinct from the T-cell-restricted SKAP55, defining its ubiquitous expression and Fyn substrate identity.

    Evidence GST-Fyn-SH2 pulldown and COS-cell kinase assays identifying SKAP-HOM/RA70 binding to Fyn, Hck, and Lyn and association with SLAP-130

    PMID:9755858 PMID:9837776

    Open questions at the time
    • Functional consequence of Fyn association not yet determined
    • Phosphorylation site not mapped
  2. 2000 Medium

    Mapped the functional phosphotyrosine, showing tyrosine 260 is required for Fyn co-association and for SKAP2's growth-inhibitory effect in myeloid progenitors.

    Evidence Site-directed Y260 mutagenesis with co-IP and retroviral overexpression colony assays in FDC-P1 and bone marrow cells

    PMID:11063873

    Open questions at the time
    • Mechanism linking phosphorylation to growth inhibition unresolved
    • Downstream effectors not identified
  3. 2005 High

    Genetic and knockdown studies placed SKAP2 downstream of membrane-proximal antigen-receptor signaling but upstream of integrin-mediated adhesion, with a function non-redundant to SKAP55.

    Evidence SKAP-HOM knockout mouse B-cell adhesion/proliferation assays and siRNA in T cells with LFA-1 clustering and conjugation readouts

    PMID:15894167 PMID:15939789 PMID:16135797

    Open questions at the time
    • Molecular link to integrin activation machinery not defined
    • Recruitment mechanism unknown
  4. 2008 High

    Resolved the structural basis of SKAP2 regulation as a PI[3,4,5]P3-gated molecular switch in which dimerization autoinhibits the PH domain until lipid binding releases it for membrane recruitment.

    Evidence X-ray crystallography of dimerization and PH domains plus phosphoinositide binding assays and ruffle-localization mutants

    PMID:19026786

    Open questions at the time
    • Kinetics of in vivo switching not measured
    • Effectors engaged after membrane recruitment not defined structurally
  5. 2009 Medium

    Extended SKAP2's integrin-adhesion role to dendritic cells, linking it to integrin-triggered actin polymerization and in vivo T-cell priming.

    Evidence SKAP-HOM knockout BMDC motility, actin polymerization, conjugate formation, and in vivo immunization assays

    PMID:19369640

    Open questions at the time
    • Direct actin-regulatory partners in DCs not identified
  6. 2010 Medium

    Defined an HPK1–SKAP2–RIAM module negatively regulating Rap1-driven integrin activation in B cells, situating SKAP2 in a defined signaling complex.

    Evidence shRNA/knockout of HPK1, Rap1 activation and adhesion assays, and co-IP in B cells

    PMID:20824186

    Open questions at the time
    • Direct vs indirect SKAP2-HPK1 contact not resolved
    • Mechanism of Rap1 control unclear
  7. 2011 High

    Identified SKAP2 as a substrate of the lymphoid phosphatase Lyp and as an HSF4b-regulated actin remodeler interacting with NCK2, establishing both its dephosphorylation and an actin-localized effector partner.

    Evidence Crystal structures of Lyp/SKAP-HOM phosphopeptide with specificity profiling; ChIP, co-IP with NCK2 SH2, and actin-remodeling knockdown in lens cells

    PMID:20219016 PMID:21719704

    Open questions at the time
    • Physiological setting of Lyp-mediated dephosphorylation not defined
    • NCK2 interaction tested largely outside immune cells
  8. 2012 High

    Established the integrin actin-remodeling mechanism: SKAP2 requires PI[3,4,5]P3 binding and Sirpα for recruitment, while also directly binding and inhibiting WAVE2-cortactin actin polymerization, revealing dual positive and negative actin control.

    Evidence Skap2-/- macrophage migration with PH-domain and Sirpα mutants; co-IP and in vitro reconstitution of WAVE2-cortactin polymerization inhibition with knockdown migration assays

    PMID:22976304 PMID:23161539

    Open questions at the time
    • How positive (Sirpα/integrin) and negative (WAVE2-cortactin) functions are spatially balanced unresolved
  9. 2015 High

    Demonstrated SKAP2's SH3-mediated WASP interaction and phosphotyrosine site are jointly required for podosome formation and macrophage invasion.

    Evidence Co-IP with WASP, podosome quantification, Skap2-/- invasion with domain-mutant rescue and in vivo metastasis model

    PMID:26577701

    Open questions at the time
    • Relationship between WASP and WAVE2 engagement not reconciled
  10. 2017 High

    Identified SKAP2 as essential for β2-integrin activation and neutrophil recruitment by regulating talin-1/kindlin-3 loading and acting through SH3-mediated WASp binding, producing a LAD-like phenotype; also extended its actin role to Arp2/3-dependent oocyte cytokinesis.

    Evidence Skap2-/- neutrophil integrin activation, talin-1/kindlin-3 co-IP, SH3 mutant analysis, intravital microscopy; siRNA depletion in oocytes with WAVE2/Arp2/3 colocalization

    PMID:28183734 PMID:28933599

    Open questions at the time
    • Direct vs indirect control of talin-1/kindlin-3 binding not biochemically resolved
  11. 2018 Medium

    Systematically mapped the SKAP2 interactome, showing dimerization modulates Src-family kinase binding and indirectly affects FYB binding, and identified FAM102A as a new partner.

    Evidence Yeast two-hybrid, co-IP, and domain mutagenesis defining binding domains of 14 interactors

    PMID:29568343

    Open questions at the time
    • Functional roles of newly mapped interactors not tested
  12. 2020 High

    Positioned SKAP2 proximal to SFK/Syk/Pyk2 activation as essential for receptor-specific neutrophil/monocyte ROS production, dissociating ROS from degranulation and Fcγ-receptor responses.

    Evidence Skap2-/- infection models (K. pneumoniae), ROS and degranulation assays, signaling intermediate phosphorylation; YopH phosphatase epistasis distinguishing integrin/GPCR vs Fcγ pathways

    PMID:32352382 PMID:32392230

    Open questions at the time
    • Direct substrate/partner mediating ROS activation not pinpointed
    • How SKAP2 selectively gates integrin/GPCR vs Fcγ pathways unclear
  13. 2021 Medium

    Broadened SKAP2 to a tissue-spanning modulator: protecting β-cells via NF-κB–iNOS–CHOP, modulating oligodendrocyte/OPC integrin-dependent migration, with a de novo PH-domain gain-of-function variant causing constitutive migration, and a further ROS role against fungal pathogens.

    Evidence INS-1E/β-cell knockdown-overexpression with CHOP epistasis; OPC KO/overexpression migration; whole-exome sequencing of p.Gly153Arg with macrophage assays; Skap2-/- neutrophil anti-Candida ROS and signaling

    PMID:33203694 PMID:34172489 PMID:34324225 PMID:34386732

    Open questions at the time
    • Whether β-cell and neuronal roles share the integrin/actin mechanism unresolved
    • Mechanism by which Gly153Arg constitutively activates not structurally confirmed
  14. 2022 High

    Defined SKAP2 as a negative regulator of TLR4-NF-κB inflammation via Sirpα/SHP-1 recruitment to TLR4 adaptors, and confirmed SH3-dependent WAVE2-ARP2/3 activation drives trophoblast growth/migration.

    Evidence Co-IPs of SKAP2 with SHP-1/Sirpα/MyD88/TIRAP/TRAM/SHP-2 with KO colitis model; W336K SH3 mutant with WAVE2/ARP2 readouts in trophoblasts; NanoBiT modular mapping of Src-family kinase binding

    PMID:35034964 PMID:36126383 PMID:36423812

    Open questions at the time
    • How the same protein switches between actin scaffolding and TLR4 inhibition is unresolved
  15. 2024 High

    Placed SKAP2 within the resting Mac-1 (CD11b/CD18) complex where it restricts adhesion at rest but enables CD18 clustering, NADPH oxidase, phagocytosis, and ADCC upon stimulation; preprint data add cell-type-specific LTB4 control.

    Evidence KINDLIN3 BioID and CD18 co-IP, CRISPR KO of SKAP2/CD18/KINDLIN3 in NB4 neutrophils with adhesion/clustering/oxidase/phagocytosis/ADCC assays; Skap2-/- LTB4 neutrophil vs macrophage comparison (preprint)

    PMID:38487529 PMID:bio_10.1101_2024.07.01.601466

    Open questions at the time
    • Molecular trigger switching SKAP2 from adhesion-restricting to clustering-promoting not defined
  16. 2025 High

    Revealed an hnRNPR–m6A–SKAP2 axis required for sperm cytoskeletal integrity and mitochondrial organization, extending SKAP2 to spermiogenesis with rescue by EV-mediated protein delivery.

    Evidence Hnrnpr mutant and germ-cell-specific Skap2 KO mice, m6A-seq, sperm morphology/motility/mitochondrial assays, EV delivery rescue

    PMID:41436426

    Open questions at the time
    • Whether sperm role uses the integrin/actin switch mechanism not established
    • Direct SKAP2 cytoskeletal partners in sperm not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single autoinhibited adaptor is selectively deployed across distinct contexts — positive actin/integrin assembly, negative WAVE2-cortactin and adhesion restriction, and TLR4-NF-κB inhibition — remains mechanistically unresolved.
  • No unified model explaining context-dependent switching between opposing SKAP2 functions
  • The direct effector immediately downstream of PI[3,4,5]P3-triggered recruitment not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3
Partners
CTTNFERMT3FYNNCK2SIRPATLN1WASPWAVE2
Complex memberships
CD11b/CD18 (Mac-1) complexSirpα/SHP-1 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SKAP-HOM (SKAP2) was identified as a novel adaptor protein purified via a GST-Fyn-SH2 domain affinity approach from pervanadate-treated EL4 cell lysates. Unlike the T-cell-specific SKAP55, SKAP-HOM is ubiquitously expressed. It does not constitutively associate with p59fyn in T cells but is a specific substrate for Fyn kinase in COS cells. It interacts with the adaptor polypeptide SLAP-130. GST-pulldown with Fyn-SH2 domain, N-terminal sequencing, molecular cloning, co-immunoprecipitation, COS cell transfection kinase assay FEBS letters Medium 9755858
1998 RA70 (SKAP2) associates with the SH2 domain of Fyn and interacts with Src family kinases Fyn, Hck, and Lyn during monocyte/macrophage differentiation of U937 cells, functioning as an adaptor for Src family kinases. Co-immunoprecipitation with SH2 domain of Fyn, expression analysis in differentiated U937 cells Biochemical and biophysical research communications Medium 9837776
2000 Murine SKAP55R (mSKAP2) is phosphorylated by FYN kinase primarily at tyrosine 260, and this phosphotyrosine is essential for co-immunoprecipitation of FYN with mSKAP55R. Enforced expression of mSKAP55R inhibited in vitro growth of myeloid FDC-P1 cells and primary hematopoietic progenitors; a Y260 mutant had no effect on growth, indicating the tyrosine phosphorylation site is required for growth inhibitory function. Transient transfection in COS cells, site-directed mutagenesis of Y260, co-immunoprecipitation, retroviral overexpression in FDC-P1 and bone marrow cells, colony assays Experimental hematology Medium 11063873
2005 Down-regulation of SKAP-55R (SKAP2) by siRNA showed it cannot substitute for SKAP-55 in TCR-mediated LFA-1 clustering and T cell-APC conjugation, demonstrating that SKAP2 has a non-redundant but distinct function from SKAP55 in inside-out integrin signaling in T cells. siRNA knockdown of SKAP55R in T cells, LFA-1 clustering assay, T cell-APC conjugation assay The Journal of experimental medicine Medium 15939789
2005 SKAP-HOM (SKAP2)-deficient mice show strongly attenuated BCR-mediated B cell proliferation and severely reduced adhesion of activated B cells to fibronectin (β1 integrin ligand) and ICAM-1 (β2 integrin ligand), while membrane-proximal BCR signaling (total tyrosine phosphorylation, Erk/p38/JNK phosphorylation, Ca2+ flux) is normal. This places SKAP2 downstream of membrane-proximal BCR signaling but upstream of integrin-mediated adhesion. SKAP-HOM knockout mouse analysis, BCR stimulation assays, adhesion assays to fibronectin and ICAM-1, flow cytometry, EAE model Molecular and cellular biology High 16135797
2005 SKAP55R (SKAP2) is expressed in myeloid cells and macrophages, is rapidly and transiently tyrosine-phosphorylated in response to M-CSF, and associates with other tyrosine-phosphorylated proteins and with actin upon M-CSF stimulation. Overexpression of SKAP55R decreased M-CSF-dependent proliferation without affecting differentiation. Western blotting for phosphorylation, co-immunoprecipitation, overexpression in myeloid cells, proliferation assays Cellular signalling Medium 15894167
2008 Crystal structure of the Skap-hom (SKAP2) dimerization and PH domains revealed that SKAP2 is a homodimer with an N-terminal four-helix bundle dimerization domain against which two PH domains pack in a conformation incompatible with phosphoinositide binding. The isolated PH domains bind PI[3,4,5]P3. Mutations disrupting the dimerization domain or the PH domain PI[3,4,5]P3-binding pocket prevent SKAP2 localization to membrane ruffles, establishing a PI[3,4,5]P3-responsive molecular switch controlling SKAP2 function. X-ray crystallography, biochemical binding assays (phosphoinositide binding), mutagenesis, cell biology (ruffle localization assays) Molecular cell High 19026786
2009 SKAP-HOM (SKAP2) in dendritic cells (DCs) is required for normal integrin-regulated DC motility and antigen-specific T cell priming in vivo. SKAP-HOM-deficient DCs show increased spontaneous motility but impaired integrin-triggered actin polymerization and reduced ability to form antigen-dependent conjugates with T cells. Immunization with SKAP-HOM-deficient BMDCs generates fewer antigen-specific T cells in vivo. SKAP-HOM knockout mouse BMDCs, in vivo LC migration assay, in vitro DC motility assay, actin polymerization assay, T cell conjugate formation assay, in vivo immunization Journal of leukocyte biology Medium 19369640
2010 HPK1 associates with SKAP-HOM (SKAP2) to negatively regulate Rap1-mediated B-lymphocyte integrin activity and LFA-1-dependent adhesion to ICAM-1. Knockdown of HPK1 increased Rap1-GTP levels and enhanced LFA-1-dependent homotypic aggregation and adhesion, downstream of Src but independent of PI3K and PLC, via a module involving HPK1, SKAP-HOM, and RIAM. shRNA knockdown of HPK1 in Wehi 231 B cells, Rap1 activation assay, adhesion assays, HPK1-/- mouse B cells, co-immunoprecipitation PloS one Medium 20824186
2011 SKAP-HOM (SKAP2) was identified as a bona fide substrate of the lymphoid-specific tyrosine phosphatase Lyp. Crystal structures of Lyp in complex with a consensus peptide and with a phosphopeptide derived from SKAP-HOM defined the molecular determinants of Lyp substrate recognition. The Lyp dephosphorylation site on SKAP-HOM was identified through substrate specificity profiling. Combinatorial library (inverse alanine scanning) for substrate motif identification, crystal structure of Lyp/SKAP-HOM phosphopeptide complex, biochemical phosphatase assays The Journal of biological chemistry High 21719704
2011 SKAP2 is a transcriptional target of HSF4b in lens epithelial cells and is highly expressed at the anterior tip of elongating lens fiber cells. SKAP2 localizes to actin-rich membrane ruffles and interacts with the SH2 domain of NCK2 via its N-terminus. The SKAP2-NCK2-F-actin complex accumulates at the lamellipodium leading edge. Knockdown of SKAP2 impairs disassembly of stress fibers in response to FGF-b, and overexpression of SKAP2 (but not the N-terminal deletion mutant) induces actin remodeling. Chromatin immunoprecipitation (ChIP) for HSF4b target, siRNA knockdown, co-immunoprecipitation of SKAP2 with NCK2 SH2 domain, immunofluorescence, overexpression of deletion mutants Journal of cellular and molecular medicine Medium 20219016
2012 Skap2 is necessary for macrophage migration, chemotaxis, global and local actin reorganization upon integrin engagement. PI[3,4,5]P3 binding to the Skap2 PH domain (relieving auto-inhibitory conformation) is critical for integrin-driven cytoskeletal response. Skap2 enables integrin-induced tyrosyl phosphorylation of SFKs, Adap, and Sirpα. Skap2 requires Sirpα for its recruitment to engaged integrins and for coordinating downstream actin rearrangement; Sirpα-deficient macrophages have identical impaired local integrin-induced responses as Skap2-/- macrophages. Skap2-/- mouse macrophage migration and chemotaxis assays, actin reorganization assays, PH domain mutants, co-immunoprecipitation/phosphorylation assays, Sirpα mutant macrophages, integrin engagement with fibronectin Journal of cell science High 22976304
2012 SKAP2 physically associates with actin assembly factors WAVE2 and cortactin and inhibits their interaction with each other. SKAP2 suppresses WAVE2-cortactin-mediated actin polymerization in vitro. Knockdown of SKAP2 in NIH3T3 cells accelerates cell migration and enhances membrane translocation of WAVE2 in a manner dependent on SKAP2-WAVE2 binding activity. Co-immunoprecipitation of SKAP2 with WAVE2 and cortactin, in vitro actin polymerization assay, siRNA knockdown, cell migration assays, WAVE2 membrane localization assay The Journal of biological chemistry High 23161539
2015 SKAP2 physically interacts with Wiskott-Aldrich syndrome protein (WASP) and localizes to podosomes in macrophages. SKAP2-null macrophages rarely form podosomes, and their invasion is significantly reduced compared to wild-type. Rescue with functional SKAP2 containing an intact tyrosine phosphorylation site and WASP-binding ability restores podosome formation and invasion, while mutants lacking these features fail to rescue. Co-immunoprecipitation of SKAP2 with WASP, immunofluorescence/podosome quantification, SKAP2-/- macrophage invasion assay, rescue with SKAP2 mutants, in vivo lung metastasis model Cancer research High 26577701
2017 Skap2 is essential for β2 integrin activation and neutrophil recruitment in vivo. Mechanistically, Skap2 regulates actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain. The direct interaction of Skap2 with WASp via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Loss of Skap2 produces a LAD-like phenotype in mice. Skap2-/- mouse neutrophil studies, β2 integrin activation assays, talin-1/kindlin-3 co-immunoprecipitation, SH3 domain mutant analysis, intravital microscopy of neutrophil recruitment The Journal of experimental medicine High 28183734
2017 SKAP2 regulates the Arp2/3 complex and is essential for actin-mediated asymmetric cytokinesis in mouse oocytes by interacting with WAVE2. SKAP2 depletion by siRNA caused failure of spindle migration, polar body extrusion, and cytokinesis defects. SKAP2 co-localizes with actin at the oocyte cortex. Depletion reduced Arp2/3 and WAVE2 expression/localization. siRNA depletion in mouse oocytes, immunofluorescence for actin/WAVE2/Arp2/3, polar body extrusion assays, cytochalasin B colocalization Cell cycle (Georgetown, Tex.) Medium 28933599
2018 The SRC-family kinase HCK shapes the SKAP2 interactome. SKAP2 dimerization modulates SRC kinase binding, with dimerization indirectly affecting FYB protein binding. Domain mapping defined 14 SKAP2 interacting proteins' binding domains/motifs and identified FAM102A as a new interactor. Fine-tuning between SRC kinase binding and their activation state was identified. Yeast two-hybrid, co-immunoprecipitation, domain mutagenesis of SKAP2, protein-protein interaction mapping Oncotarget Medium 29568343
2020 SKAP2 is required for protection against K. pneumoniae pulmonary infection by enabling neutrophil and monocyte ROS production. SKAP2-/- neutrophils and monocytes are present in infected lungs and degranulate normally, but K. pneumoniae-stimulated ROS production in vitro is abolished. K. pneumoniae-induced neutrophil ROS requires SFKs, Syk, Btk, PLCγ2, and PKC. Loss of SKAP2 significantly impairs phosphorylation of SFKs, Syk, and Pyk2, placing SKAP2 proximal to their activation. Skap2-/- mouse infection model, ROS assays (DHR), degranulation assays, Western blotting of signaling intermediates, in vitro neutrophil stimulation with K. pneumoniae eLife High 32352382
2020 YopH (Yersinia tyrosine phosphatase effector) dephosphorylates SKAP2 in neutrophils. SKAP2 is required for integrin receptor- and GPCR-mediated ROS production but is dispensable for degranulation under all conditions tested. YopH also blocks SKAP2-independent FcγR-stimulated phosphorylation of Syk, SLP-76, PLCγ2, and ERK1/2. These findings uncouple integrin/GPCR-dependent ROS from FcγR responses based on SKAP2 dependency. Skap2KO mouse neutrophils, YopH deletion mutant Yersinia infection, ROS assays, degranulation assays, phosphorylation analysis of signaling intermediates, Skap2KO vs WT comparison PLoS pathogens High 32392230
2021 SKAP2 controls β-cell sensitivity to cytokine-induced apoptosis. Knockdown of SKAP2 aggravated cytokine-induced apoptosis in INS-1E cells and primary rat β-cells; overexpression afforded protection against cytokine-induced apoptosis. This correlated with reduced nuclear NF-κB p65 (S536-phosphorylated), lower nitric oxide production, and diminished CHOP expression. Knockdown of CHOP partially reversed the increased apoptosis caused by SKAP2 knockdown, linking SKAP2 to the NF-κB-iNOS-ER stress pathway. siRNA knockdown and overexpression in INS-1E cells and rat β-cells, apoptosis assays, NF-κB p65 nuclear translocation/phosphorylation assays, NO measurement, CHOP expression, double knockdown epistasis Diabetes Medium 33203694
2021 SKAP2 downregulation or complete lack impairs OPC migration and morphological maturation in oligodendrocytes. Overexpression of SKAP2 or constitutively active SKAP2 increased OPC migration, suggesting SKAP2 function depends on phosphorylation-based activation. Lack of SKAP2 enhanced the positive effect of integrin activation on OPC migration, indicating SKAP2 acts as a modulator of integrin-dependent migration in oligodendrocytes. SKAP2 KO OPCs, siRNA knockdown, overexpression of constitutively active SKAP2, migration assays, morphological maturation analysis, integrin activation experiments Glia Medium 34324225
2021 A de novo gain-of-function SKAP2 variant (p.Gly153Arg), located in the well-conserved lipid-binding loop of the PH domain, leads to enhanced integrin pathway activity and constitutive migratory behavior in myeloid macrophages in the absence of chemokine stimulation, consistent with constitutive SKAP2 activation. Whole-exome sequencing, monocyte-derived macrophage functional assays from patient and family members, integrin pathway activation assays, migration assays, expression of p.Gly153Arg variant in human macrophage cell line Diabetes care Medium 34172489
2021 SKAP2 is required for maximal ROS production by neutrophils in response to C-type lectin receptor (CLR) agonists and fungal pathogens (Candida glabrata and Candida albicans), and for robust killing of C. glabrata. Inside-out integrin signaling and Syk phosphorylation occur independently of SKAP2 after Candida infection. However, Pyk2, ERK1/2, and p38 phosphorylation are significantly reduced in Skap2-/- neutrophils after Candida and K. pneumoniae infection. HoxB8-immortalized Skap2-/- neutrophil progenitors, ROS assays, killing assays, phosphorylation analysis of Syk/Pyk2/ERK1/2/p38, inside-out integrin signaling assay iScience Medium 34386732
2022 SKAP2 forms a complex with the Sirpα transmembrane receptor and the SHP-1 tyrosine phosphatase, and directly associates with the TIR domain of TLR4 adaptors MyD88, TIRAP, and TRAM. SKAP2-mediated recruitment of the Sirpα/SHP-1 complex to TLR4 attenuates NF-κB inflammatory signaling, while direct SKAP2 interaction with SHP-2 decreases SHP-2 activation. This dual mechanism inhibits NF-κB while promoting the TLR4-IFNβ pathway. Co-immunoprecipitation (SKAP2 with SHP-1, Sirpα, MyD88/TIRAP/TRAM, SHP-2), SKAP2 knockout mice in colitis/tumorigenesis model, NF-κB activation assays, cytokine measurements, overexpression studies Oncogene High 35034964
2022 SKAP2 activates the WAVE2-ARP2/3 pathway in trophoblasts to promote cell growth and migration. SKAP2 W336K mutant (SH3 domain-blocked) cannot alter WAVE2 and ARP2 expression or HTR8/SVneo cell growth and migration, demonstrating that the SH3 domain of SKAP2 is required for its interaction with and activation of WAVE2-ARP2/3 signaling. siRNA knockdown and overexpression in HTR8/SVneo trophoblast cells, W336K SH3 domain mutant, western blotting for WAVE2/ARP2, immunofluorescence for actin-WAVE2 colocalization, cell growth (CCK8) and migration (transwell) assays Placenta Medium 36126383
2022 SKAP2 interacts with SRC kinases through a modular organization comprising three interacting modules: the dimerization domain, the SH3 domain, and the second interdomain (between PH and SH3). The dimerization domain is necessary and sufficient to bind most activated and myristylated SRC kinases, while all three modules are required to bind SRC kinases at steady state. SKAP2 dimerization induces increased binding for most SRC kinases. Tyrosines in the interdomains modulate these interactions. Luciferase complementation assay (NanoBiT), extensive site-directed mutagenesis of SKAP2 domains, analysis of SRC kinase family member HCK mutants (Y390, K7) Molecular & cellular proteomics : MCP Medium 36423812
2024 SKAP2 is present in the CD11b/CD18 (Mac-1) complex at steady state in primary and NB4 neutrophils, identified by KINDLIN3 BioID proximity labeling and confirmed by CD18 immunoprecipitation. Under resting conditions (without stimulation), SKAP2 restricts CD11b/CD18-mediated adhesion. Upon stimulation, SKAP2 is required for CD18 clustering, NADPH oxidase activity, phagocytosis, and cytotoxicity against tumor cells (ADCC). SKAP2-deficient NB4 neutrophils show enhanced resting adhesion to fibronectin but strongly reduced CD18 clustering upon stimulation. BioID proximity labeling of KINDLIN3 interactome, CD18 co-immunoprecipitation, CRISPR-Cas9 KO of SKAP2/CD18/KINDLIN3 in NB4 cells, adhesion assays, CD18 clustering by microscopy, NADPH oxidase activity, phagocytosis, ADCC assays Frontiers in immunology High 38487529
2014 Ra70/Scap2 (SKAP2) is expressed in the ependymal layer and ventricular zone of the neural tube during development (E7.5-11.5) in heterozygous LacZ-knockin mice, restricted to posterior neural tissues including neural tube and hindbrain. Homozygous Ra70/scap2 knockout mice die during embryogenesis, indicating SKAP2 is essential for embryonic development. LacZ knockin heterozygous and homozygous knockout mouse analysis, immunohistochemistry, RNA expression analysis in P19 EC cells during RA-induced neuronal differentiation Neuroscience letters Medium 24846415
2025 SKAP2 is required for sperm cytoskeletal structure and mitochondrial organization during spermiogenesis. Hnrnpr mutation disrupts m6A-dependent splicing of Skap2 pre-mRNA, impairing SKAP2 protein production in sperm and causing motility decline and morphological abnormalities. Specific knockout of Skap2 in male germ cells phenocopies these defects. Extracellular vesicle-mediated delivery of SKAP2 to efferent ductules restores sperm motility and morphology, confirming the functional hnRNPR-SKAP2 axis. Hnrnpr mutant mice and human patients, germ cell-specific Skap2 KO mice, sperm motility and morphology analysis, mitochondrial organization assays, m6A-seq for splice site, extracellular vesicle delivery rescue experiment Signal transduction and targeted therapy High 41436426
2024 SKAP2/PLC signaling pathway is essential for LTB4 production by neutrophils in response to bacterial T3SS stimulation, but is not required for LTB4 synthesis by macrophages (which instead requires phagocytosis and NLRP3/CASP1 inflammasome), establishing cell-type-specific pathway requirements for LTB4 synthesis. Skap2-/- mouse neutrophils and macrophages, LTB4 production assays with T3SS stimulation, pharmacological inhibitors of signaling intermediates, NLRP3/CASP1 pathway analysis bioRxivpreprint Medium bio_10.1101_2024.07.01.601466

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. The EMBO journal 180 14657016
1999 Characterization of a protein complex containing spliceosomal proteins SAPs 49, 130, 145, and 155. Molecular and cellular biology 117 10490618
2008 Nano scale proteomics revealed the presence of regulatory proteins including three FT-Like proteins in phloem and xylem saps from rice. Plant & cell physiology 112 18372294
2019 The use of APACHE II, SOFA, SAPS 3, C-reactive protein/albumin ratio, and lactate to predict mortality of surgical critically ill patients: A retrospective cohort study. Medicine 86 31261567
2013 SAPs as novel regulators of abiotic stress response in plants. BioEssays : news and reviews in molecular, cellular and developmental biology 84 23640876
1998 SKAP-HOM, a novel adaptor protein homologous to the FYN-associated protein SKAP55. FEBS letters 74 9755858
2005 Regulation of in vitro and in vivo immune functions by the cytosolic adaptor protein SKAP-HOM. Molecular and cellular biology 70 16135797
2012 Macrophages require Skap2 and Sirpα for integrin-stimulated cytoskeletal rearrangement. Journal of cell science 55 22976304
2017 Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions. The Journal of experimental medicine 54 28183734
2014 Rice SAPs are responsive to multiple biotic stresses and overexpression of OsSAP1, an A20/AN1 zinc-finger protein, enhances the basal resistance against pathogen infection in tobacco. Plant science : an international journal of experimental plant biology 49 25017161
2005 An essential role for SKAP-55 in LFA-1 clustering on T cells that cannot be substituted by SKAP-55R. The Journal of experimental medicine 48 15939789
2002 Individual acid aspartic proteinases (Saps) 1-6 of Candida albicans are not essential for invasion and colonization of the gastrointestinal tract in mice. Microbial pathogenesis 48 11812212
2016 Genome-wide identification and expression analysis of stress-associated proteins (SAPs) containing A20/AN1 zinc finger in cotton. Molecular genetics and genomics : MGG 40 27681253
2008 The Skap-hom dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch. Molecular cell 40 19026786
2015 SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression. Cancer research 34 26577701
2018 From the sap's perspective: The nature of vessel surfaces in angiosperm xylem. American journal of botany 33 29578294
2020 SKAP2 is required for defense against K. pneumoniae infection and neutrophil respiratory burst. eLife 29 32352382
2021 The Multiple Roles of the Cytosolic Adapter Proteins ADAP, SKAP1 and SKAP2 for TCR/CD3 -Mediated Signaling Events. Frontiers in immunology 28 34295339
2020 Identification and Expression Analysis of Stress-Associated Proteins (SAPs) Containing A20/AN1 Zinc Finger in Cucumber. Plants (Basel, Switzerland) 28 32213813
2011 Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate. The Journal of biological chemistry 28 21719704
1998 RA70 is a src kinase-associated protein expressed ubiquitously. Biochemical and biophysical research communications 28 9837776
2011 SKAP2, a novel target of HSF4b, associates with NCK2/F-actin at membrane ruffles and regulates actin reorganization in lens cell. Journal of cellular and molecular medicine 27 20219016
2010 Dieldrin-dissolving abilities of the xylem saps of several plant families, particularly Cucurbita pepo L. Environmental toxicology and chemistry 27 20872691
2022 SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 26 35034964
2014 Role of Candida albicans-secreted aspartyl proteinases (Saps) in severe early childhood caries. International journal of molecular sciences 25 24933640
1997 Accumulation of sphingolipid activator proteins (SAPs) A and D in granular osmiophilic deposits in miniature Schnauzer dogs with ceroid-lipofuscinosis. Journal of inherited metabolic disease 25 9061571
1997 Sphingolipid activator proteins (SAPs) in neuronal ceroid lipofuscinoses (NCL). Neuropediatrics 24 9151322
2009 Expression of SKAP-HOM in DCs is required for an optimal immune response in vivo. Journal of leukocyte biology 23 19369640
2000 Adaptor protein SKAP55R is associated with myeloid differentiation and growth arrest. Experimental hematology 23 11063873
2021 SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation. Glia 22 34324225
2021 Spermidine Induces Expression of Stress Associated Proteins (SAPs) Genes and Protects Rice Seed from Heat Stress-Induced Damage during Grain-Filling. Antioxidants (Basel, Switzerland) 21 34679679
2020 Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection. PLoS pathogens 21 32392230
2012 The Src substrate SKAP2 regulates actin assembly by interacting with WAVE2 and cortactin proteins. The Journal of biological chemistry 21 23161539
2010 HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion. PloS one 19 20824186
2012 Molecular basis for population variation: from SNPs to SAPs. FEBS letters 18 22828278
2005 Macrophage colony-stimulating factor receptor induces tyrosine phosphorylation of SKAP55R adaptor and its association with actin. Cellular signalling 18 15894167
2009 Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical repeats. BMC biochemistry 16 19835610
2005 Genetic analysis of Bacillus anthracis Sap S-layer protein crystallization domain. Microbiology (Reading, England) 16 15870458
1998 Sequence-assisted peptide synthesis (SAPS). The journal of peptide research : official journal of the American Peptide Society 16 9924991
1990 Antifungal action of latex saps from Lactuca sativa L. and Asclepias curassavica L. Mycoses 16 2090937
2023 SKAP2-A Molecule at the Crossroads for Integrin Signalling and Immune Cell Migration and Function. Biomedicines 15 37893161
2021 Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation. Diabetes care 14 34172489
2016 High intravascular tissue factor-but not extracellular microvesicles-in septic patients is associated with a high SAPS II score. Journal of intensive care 13 27217958
1995 Sphingolipid activator proteins (SAPs) are stored together with glycosphingolipids in the infantile neuronal ceroid-lipofuscinosis (INCL). American journal of medical genetics 13 7668348
2022 Identification, Phylogeny, Divergence, Structure, and Expression Analysis of A20/AN1 Zinc Finger Domain Containing Stress-Associated Proteins (SAPs) Genes in Jatropha curcas L. Genes 12 36292651
2021 Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation. iScience 12 34386732
2020 SKAP2, a Candidate Gene for Type 1 Diabetes, Regulates β-Cell Apoptosis and Glycemic Control in Newly Diagnosed Patients. Diabetes 12 33203694
2021 Considerations on the Demography of BIA-ALCL in European Countries Based on an E(A)SAPS Survey. Aesthetic plastic surgery 11 34286385
2017 SKAP2 regulates Arp2/3 complex for actin-mediated asymmetric cytokinesis by interacting with WAVE2 in mouse oocytes. Cell cycle (Georgetown, Tex.) 11 28933599
2021 SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy. BMJ case reports 10 34167970
2022 SKAP2 is downregulated in the villous tissues of patients with missed abortion and regulates growth and migration in trophoblasts through the WAVE2-ARP2/3 signaling pathway. Placenta 9 36126383
2022 SKAP2 Modular Organization Differently Recognizes SRC Kinases Depending on Their Activation Status and Localization. Molecular & cellular proteomics : MCP 9 36423812
2018 The SRC-family tyrosine kinase HCK shapes the landscape of SKAP2 interactome. Oncotarget 9 29568343
2023 Autofluorescence imaging permits label-free cell type assignment and reveals the dynamic formation of airway secretory cell associated antigen passages (SAPs). eLife 8 36994985
2024 SKAP2 acts downstream of CD11b/CD18 and regulates neutrophil effector function. Frontiers in immunology 7 38487529
2024 Architecture of the Sap S-layer of Bacillus anthracis revealed by integrative structural biology. Proceedings of the National Academy of Sciences of the United States of America 7 39652757
2022 Characterization of the Secreted Acid Phosphatase SapS Reveals a Novel Virulence Factor of Staphylococcus aureus That Contributes to Survival and Virulence in Mice. International journal of molecular sciences 6 36430506
2017 Subcutaneous accessory pain system (SAPS): A novel pain pathway for myofascial trigger points. Medical hypotheses 6 29406997
1991 Glycosidic activities of Candida albicans after action of vegetable latex saps (natural antifungals) and isoconazole (synthetic antifungal). Mycoses 6 1922192
2025 Targeting SKAP2 restores sperm motility and morphology through modulating mitochondrial organization and cytoskeletal remodeling. Signal transduction and targeted therapy 5 41436426
2023 Molecular Detection of Secreted Aspartyl Proteinases (Saps) From Dental Isolates of Candida albicans and Targeting With Psidium guajava Biocompounds: An In Vitro and In Silico Analysis. Cureus 5 38130563
2022 Dynamics of microbial populations and metabolites of fermenting saps throughout tapping process of ron and oil palm trees in Côte d'Ivoire. Frontiers in microbiology 4 36386638
2021 Genome-Wide Identification of Stress-Associated Proteins (SAPs) Encoding A20/AN1 Zinc Finger in Almond (Prunus dulcis) and Their Differential Expression during Fruit Development. Plants (Basel, Switzerland) 4 35009120
2020 Characterization of Soluble Algal Products (SAPs) after electrocoagulation of a mixed algal culture. Biotechnology reports (Amsterdam, Netherlands) 4 32090025
2020 Score performance of SAPS 2 and SAPS 3 in combination with biomarkers IL-6, PCT or CRP. PloS one 4 32881963
2015 CoagVDb: a comprehensive database for coagulation factors and their associated SAPs. Biological research 4 26187044
2024 Developing Augmented Pro-SOFA and Pro-SAPS Models by Integrating Biomarkers PCT, NLR, and CRP with SOFA and SAPS-III Scores. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine 3 39411306
2023 Shearing of surface mucin saps tumor cell strength. Trends in pharmacological sciences 3 37679271
2024 Extracellular BSA-degrading SAPs in the rare pathogen Meyerozyma guilliermondii strain SO as potential virulence factors in candidiasis. Microbial pathogenesis 2 38960213
2021 SAPs as a new model to probe the pathway of centriole and centrosome assembly. Biochemical Society transactions 2 33960367
2014 Hippocampus-dependent learning in SKAP-HOM deficient mice. Behavioural brain research 2 24815314
2014 Spatial and temporal expression of RA70/Scap2 in the developing neural tube. Neuroscience letters 2 24846415
2001 NF-Y regulates LIF-induced transcription of the signaling adaptor SKAP55R in myeloid cells. Leukemia 2 11753615
2026 Stress-associated proteins (SAPs): Molecular hubs connecting plant stress, development, and metabolism. Plant science : an international journal of experimental plant biology 1 41490590
2025 Predictive Performance of SAPS-3, SOFA Score, and Procalcitonin for Hospital Mortality in COVID-19 Viral Sepsis: A Cohort Study. Life (Basel, Switzerland) 1 40868809
2025 MAPK3 modulates enhancer-promoter interactions of SKAP2 in acute myeloid leukemia. Carcinogenesis 1 41139207
2024 Role of two modules controlling the interaction between SKAP1 and SRC kinases comparison with SKAP2 architecture and consequences for evolution. PloS one 1 38483858
2023 Detection and expression of SapS, a class C nonspecific acid phosphatase with O-phospho-Ltyrosine- phosphatase activity, in Staphylococcus aureus isolates from patients with chronic osteomyelitis. Biomedica : revista del Instituto Nacional de Salud 1 37433170
2026 Genome-wide identification and expression analysis of stress-associated proteins (SAPs) containing A20/AN1 Zinc finger in Dendrobium officinale. BMC plant biology 0 41629782
2026 Genome-wide identification and characterization of the stress-associated proteins (SAPs) gene family in Amaranthus palmeri S. Watson. Molecular biology reports 0 41945173
2026 Gain-of-function mutation in SKAP2 leads to type 1 diabetes and broader autoimmunity through hyperactive integrin signaling in myeloid cells. bioRxiv : the preprint server for biology 0 41993266
2025 Expression and Regulatory Roles of SKAP2 and Cortactin in Mouse Ovarian Tissue and Oocyte Maturation. Reproductive sciences (Thousand Oaks, Calif.) 0 40629241
2025 APACHE II, SOFA, and SAPS III after transhiatal and thoracoscopic in prone position esophagectomy for esophageal cancer: a single-center retrospective cohort analysis. Arquivos brasileiros de cirurgia digestiva : ABCD = Brazilian archives of digestive surgery 0 41660937

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