Affinage

SHB

SH2 domain-containing adapter protein B · UniProt Q15464

Length
509 aa
Mass
55.0 kDa
Annotated
2026-06-10
67 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHB is a ubiquitously deployed SH2/PTB-domain adaptor protein that couples activated tyrosine kinase receptors to cytoskeletal, survival, and migratory effector pathways across vascular, neuronal, endocrine, and immune cells (PMID:8302579, PMID:15026417, PMID:32060095). Its SH2 domain recognizes a pTyr-Thr/Val/Ile-X-Leu motif and docks onto specific phosphotyrosines of multiple receptors—the PDGF β- and α-receptors, FGFR-1 Y766, VEGFR-2 Y1175, and IL-2Rβ Y510—while its PTB domain reads a Asp-Asp-X-pTyr sequence and its proline-rich motifs engage SH3-domain partners including Src, p85α PI3-kinase, Grb2, and the JAK kinases (PMID:7537362, PMID:9484780, PMID:10837138, PMID:12181353, PMID:12200137, PMID:15026417). Through these modular interactions SHB nucleates multiprotein complexes that activate FAK, PI3-kinase/Akt, Rac1, Rap1, and PLC-γ/MAPK signaling, thereby controlling focal adhesion turnover, stress-fiber and ruffle formation, and directed cell migration (PMID:10837138, PMID:12520086, PMID:12464388, PMID:15026417). In endothelial cells SHB is recruited to VEGFR-2 within minutes of VEGF-A stimulation and relays the receptor to FAK to drive focal-adhesion assembly, PI3-kinase activation, junctional VE-cadherin remodeling, and angiogenesis, with Shb-null mice showing dysregulated vascular permeability and impaired tumor angiogenesis (PMID:15026417, PMID:23000345, PMID:31847469, PMID:19223532). SHB also functions as a context-dependent regulator of cell fate: it transduces apoptotic signals downstream of select receptors and from endostatin, while supporting survival downstream of IL-2 and the viral protein LMP2A (PMID:8806685, PMID:10828022, PMID:12200137, PMID:17311000). In T cells SHB localizes to lipid rafts and links the TCR ζ-chain and ZAP70 to the LAT/SLP-76/Gads/Vav/PLC-γ1 machinery to drive Ca2+/NFAT signaling and IL-2 production (PMID:9484780, PMID:10488157, PMID:12084069). Across multiple physiological settings SHB acts as a negative regulator of basal FAK activity, with its loss elevating FAK signaling in pancreatic β-cells, hematopoietic stem cells, and leukemic cells, explaining its in vivo roles in insulin secretion, stem-cell quiescence, and tumor progression (PMID:23528453, PMID:25274988, PMID:24952416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1994 Medium

    Established SHB as a receptor-tyrosine-kinase adaptor by showing its SH2 domain selectively binds the activated PDGF β-receptor and not the EGF receptor, defining the founding molecular activity of the protein.

    Evidence GST-SH2 pull-down and Western blot following cDNA cloning and transfection

    PMID:8302579

    Open questions at the time
    • Did not define the phosphopeptide specificity of the SH2 domain
    • No functional cellular consequence established
  2. 1995 High

    Defined the binding code of SHB—SH2 recognition of a pTyr-Thr/Val/Ile-X-Leu motif on PDGFR and FGFR-1, and proline-rich engagement of Src, p85 PI3-kinase, and Eps8 SH3 domains—mapping how SHB bridges receptors to downstream effectors.

    Evidence Degenerate phosphopeptide library, receptor Y→F mutants, GST-SH3 pull-down and co-IP

    PMID:7537362

    Open questions at the time
    • In vitro binding specificity not yet linked to a signaling output
    • Stoichiometry and competition among proline-rich partners unresolved
  3. 1996 Medium

    Showed SHB can transduce apoptotic signals downstream of specific RTKs, revealing a pro-death function rescuable by PDGF-BB but not IGF-1.

    Evidence Stable overexpression in NIH3T3, serum deprivation, TUNEL, growth factor rescue

    PMID:8806685

    Open questions at the time
    • Overexpression artifact not excluded
    • Molecular effectors of the apoptotic signal not identified
  4. 1998 Medium

    Extended SHB function to neurotrophic signaling, demonstrating SH2-dependent enhancement of NGF/bFGF-induced neurite outgrowth and association with an NGF-activated 140-kDa phosphoprotein.

    Evidence Stable PC12 transfection, neurite outgrowth assay, co-IP, R522K SH2 mutant

    PMID:9751119

    Open questions at the time
    • Identity of the 140-kDa partner not established
    • Downstream pathway not yet mapped
  5. 1998 High

    Placed SHB at the proximal TCR signalosome by mapping SH2 binding to the TCR ζ-chain, PTB binding to a Lnk-related protein via a Asp-Asp-X-pTyr motif, and proline-rich binding to Grb2.

    Evidence Co-IP, phosphopeptide library, competing peptides, dominant-negative R522K

    PMID:9484780

    Open questions at the time
    • Functional consequence for T-cell activation not yet measured
    • PTB partner p36/38 identity not definitively assigned
  6. 1999 High

    Defined SHB as an upstream organizer of the LAT/PLC-γ1 axis in T cells, with dominant-negative SHB blocking Ca2+ flux, NFAT activation, and IL-2 production.

    Evidence Co-IP, dominant-negative overexpression, calcium imaging, NFAT reporter, IL-2 ELISA

    PMID:10488157

    Open questions at the time
    • Endogenous requirement (vs dominant-negative) not tested
    • Direct vs indirect LAT recruitment unresolved
  7. 2000 Medium

    Connected SHB to Rap1-dependent neurite outgrowth via GTK/FRK-induced SHB phosphorylation and SHB/FAK/CrkII complex formation.

    Evidence Co-IP, phospho-Western, Rap1 pathway inhibitors (RalGDS-RBD, Rap1GAP), neurite assay in PC12

    PMID:10878015 PMID:10964504

    Open questions at the time
    • Direct enzymatic link from SHB complex to Rap1 GEF not defined
    • Overexpression context dependence
  8. 2000 Medium

    Revealed a cytoskeletal-regulatory role for SHB at the PDGF-α receptor (binding Y720), where it suppresses ruffling and Rac activation while promoting filopodia, dissociating its effects from PI3-kinase/Akt.

    Evidence Co-IP, R522K mutant, Rac activation assay, PI3-kinase assay, cytoskeletal imaging in fibroblasts

    PMID:10837138

    Open questions at the time
    • Mechanism by which SHB lowers Rac activity not defined
    • Single overexpression cell system
  9. 2000 Medium

    Implicated SHB in endostatin-driven endothelial apoptosis, showing endostatin induces SHB phosphorylation and that a functional SHB SH2 domain is required for FGF-2-treated endothelial cell death.

    Evidence GST-SH2 pull-down, in vitro kinase assay, SH2 mutant, apoptosis assay in endothelial cells

    PMID:10828022

    Open questions at the time
    • Identity of the 125-kDa SHB-associated kinase unresolved
    • Receptor mediating endostatin-to-SHB signal unknown
  10. 2002 High

    Established SHB as the adaptor linking FGFR-1 Y766 to FRS2 phosphorylation and Ras/MAPK mitogenic signaling.

    Evidence Chimeric receptor with Y766F, SH2 mutant epistasis, FRS2 and MAPK phosphorylation, mitogenicity assay

    PMID:12181353

    Open questions at the time
    • Whether SHB directly phosphorylates/recruits FRS2 not resolved
    • Generalization beyond chimeric receptor system
  11. 2002 High

    Resolved the TCR signalosome architecture, showing SHB localizes to lipid rafts and recruits the SLP-76/Gads/Vav complex to the ζ-chain/ZAP70, controlling Vav phosphorylation and JNK activation.

    Evidence Co-IP, GST domain mapping, lipid raft fractionation, dominant-negative, JNK assay in Jurkat

    PMID:12084069

    Open questions at the time
    • Endogenous SHB requirement not tested by knockdown
    • Direct vs scaffolded contacts not fully separated
  12. 2002 Medium

    Showed SHB couples receptors to survival and metabolic signaling by binding IL-2Rβ Y510 and JAK1/3 to promote IL-2-dependent survival, and by assembling an IRS-1/IRS-2/FAK/PI3-kinase complex that elevates Akt in β-cells.

    Evidence Co-IP, GST pull-down, IL-2Rβ Y→F mutants, apoptosis assay; co-IP and kinase assay in islets/RINm5F

    PMID:12200137 PMID:12520086

    Open questions at the time
    • Direct vs indirect JAK and IRS contacts not separated
    • Physiological stoichiometry in primary cells unclear
  13. 2003 High

    Defined the SHB-FAK link as a PTB-mediated direct interaction in endothelial cells, with Src (not FAK) responsible for FGF-2-induced SHB phosphorylation, promoting FAK phosphorylation and cell spreading.

    Evidence Co-IP, PTB mutant, Src inhibitor, temperature-sensitive v-Src, spreading assay

    PMID:12464388

    Open questions at the time
    • Whether SHB activates FAK directly or via complex assembly unresolved
  14. 2004 High

    Defined SHB as the obligate VEGFR-2 Y1175 adaptor driving angiogenic signaling, with knockdown abolishing VEGF-induced PI3-kinase, FAK phosphorylation, focal adhesion/stress fiber formation, and migration.

    Evidence GST pull-down, co-IP, VEGFR-2 Y1175 mutant, siRNA knockdown, multiple functional readouts in endothelial cells

    PMID:15026417

    Open questions at the time
    • In vivo vascular consequence not yet tested
    • Temporal kinetics of recruitment unresolved
  15. 2006 Medium

    Identified a bidirectional SHB–c-Abl relationship in which SHB binds c-Abl SH3/SH2 domains, regulates c-Abl kinase activity, and modulates genotoxic/ER-stress-induced cell death.

    Evidence Co-IP, kinase assay, siRNA/shRNA knockdown, apoptosis with cisplatin/tunicamycin

    PMID:17112510

    Open questions at the time
    • Direction of causality between SHB and c-Abl in death not fully resolved
    • Single cell-context dependence
  16. 2007 High

    Showed SHB mediates oncogenic signaling from the EBV LMP2A ITAM, where SH2/PTB binding sustains constitutive Akt activation and regulates Syk stability.

    Evidence Co-IP, SH2/PTB domain mutations, shRNA knockdown, Akt assay

    PMID:17311000

    Open questions at the time
    • Mechanism linking SHB to PI3-kinase/Akt in LMP2A cells not fully mapped
  17. 2007 Medium

    Demonstrated SHB promotes endothelial tumor cell survival and FAK signaling in vivo, with knockdown sensitizing angiosarcoma cells to apoptosis and reducing tumor growth.

    Evidence Inducible shRNA knockdown, apoptosis and FAK phosphorylation assays, in vivo tumor model

    PMID:17914455

    Open questions at the time
    • Whether reduced FAK phosphorylation directly causes apoptosis not isolated
  18. 2009 Medium

    Provided the first in vivo physiology for SHB through knockout mice, revealing dysregulated basal and VEGF-stimulated vascular permeability, endothelial cytoskeletal/ultrastructural defects, and impaired tumor angiogenesis, plus impaired β-cell insulin secretion and islet microvasculature.

    Evidence Shb knockout mice, permeability assays, EM, Matrigel angiogenesis, pancreas perfusion, patch-clamp capacitance

    PMID:19223532 PMID:19696098

    Open questions at the time
    • Cell-autonomous vs systemic contributions not separated
    • Molecular link to capacitance/secretion defect not yet defined
  19. 2010 Medium

    Revealed a reproductive role: SHB restrains ERK/RSK/S6 signaling in oocytes, with its loss accelerating oogenesis but impairing follicle maturation and embryo development.

    Evidence Shb knockout mouse, IVF, live-cell meiosis imaging, phospho-Western

    PMID:20585392

    Open questions at the time
    • Receptor upstream of SHB in oocytes not identified
    • Mechanism of ERK/RSK restraint unresolved
  20. 2011 Medium

    Showed SHB tunes T-cell activation thresholds in vivo, with knockout raising basal TCR activation, enhancing proliferation, and skewing toward Th2/IL-4.

    Evidence Shb knockout mouse, phospho-flow, proliferation and cytokine assays

    PMID:21223549

    Open questions at the time
    • Molecular basis of elevated basal TCR signaling not pinned down
  21. 2012 Medium

    Demonstrated SHB is required for VEGF-A-dependent endothelial junctional remodeling and downstream ERK/Akt/Rac1 activation, with knockout cells failing to redistribute VE-cadherin/VEGFR-2 at adherens junctions.

    Evidence Primary Shb-null lung endothelial cells, confocal imaging, Rac1 assay, phospho-Western

    PMID:23000345

    Open questions at the time
    • Direct molecular link from SHB to VE-cadherin complex not defined
  22. 2012 Medium

    Extended the SHB/LMP2A complex by showing SHB simultaneously bridges LMP2A phosphotyrosines to ITSN1 SH3 domains, with Syk and Lyn phosphorylating SHB.

    Evidence Co-IP, Syk/Lyn kinase inhibitors, phospho-Western

    PMID:22975684

    Open questions at the time
    • Functional output of the ITSN1-SHB-LMP2A complex not established
  23. 2013 Medium

    Established SHB as a negative regulator of FAK/Rac1/PAK in hematopoietic stem cells, controlling LT-HSC cell cycle, with FAK inhibition rescuing the knockout proliferation phenotype.

    Evidence Shb knockout mouse, bone marrow transplantation, FAK inhibitor, phospho-Western

    PMID:23528453

    Open questions at the time
    • How SHB restrains basal FAK activity mechanistically unresolved
  24. 2014 High

    Unified the SHB-FAK negative-regulation theme in disease and metabolism: in β-cells SHB loss elevates basal FAK/IRS/Akt and β-catenin and delays cAMP/insulin exocytosis, while in BCR-ABL leukemia SHB loss raises FAK activity and accelerates cell-intrinsic, FAK-dependent leukemic expansion.

    Evidence Shb knockout mouse, live-cell cAMP imaging, patch-clamp, FAK inhibitor; retroviral BCR-ABL transformation and transplantation

    PMID:24952416 PMID:25274988

    Open questions at the time
    • Direct biochemical mechanism by which SHB suppresses basal FAK still undefined
    • Whether β-catenin elevation is FAK-dependent not isolated
  25. 2019 High

    Resolved the spatiotemporal mechanism of SHB at VEGFR-2, showing Y1175-dependent co-localization within <2.5 min and SHB-dependent recruitment of FAK to the receptor, with SHB loss redistributing focal adhesions.

    Evidence Live-cell TIRF microscopy, VEGFR2 Y1175F mutant, primary Shb-null endothelial cells

    PMID:31847469

    Open questions at the time
    • Structural basis of the ternary VEGFR2/SHB/FAK assembly not determined
  26. 2020 High

    Defined SHB as a conserved Eph-receptor scaffold for cytoskeletal segregation, mapping phosphotyrosines that recruit Nck (Y297), RasGAP (Y246), and Chimaerin Rac-GAPs (Y336), and demonstrated cell-type-specific vascular roles via conditional knockouts.

    Evidence Co-IP with Shb Y-mutants, HEK293 cell segregation assay, multiple Eph receptors; conditional pericyte/endothelial Cre-lox knockouts with metastasis and permeability readouts

    PMID:32060095 PMID:32441314

    Open questions at the time
    • How simultaneous GAP recruitment is spatially coordinated unresolved
    • Pericyte vs endothelial signaling integration in tumors incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct biochemical mechanism by which SHB restrains basal FAK activity—and the structural basis for its multivalent assembly of GAPs, kinases, and effectors at distinct receptors—remains unresolved.
  • No structural model of SHB or its complexes
  • Mechanism of FAK suppression undefined
  • Quantitative competition among SHB partners not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3
Partners
C-ABLFAKFGFR1NCKPDGFRARASA1SRCVEGFR2
Complex memberships
IRS-1/IRS-2/FAK/PI3-kinase complexTCR signalosome (ζ-chain/ZAP70/LAT/SLP-76/Gads/Vav/PLC-γ1)VEGFR-2/SHB/FAK complexlipid raft microdomain signaling complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 SHB was identified as a novel SH2-containing adaptor protein with proline-rich domains. The SH2 domain of SHB binds specifically to the autophosphorylated PDGF β-receptor but not the EGF receptor in GST pull-down assays, establishing SHB as a signal transduction adaptor linking SH3 domain proteins to tyrosine kinases. GST-SH2 fusion protein pull-down, Western blot, cDNA cloning, transient transfection Oncogene Medium 8302579
1995 The SHB SH2 domain preferentially binds the phosphopeptide motif pTyr-Thr/Val/Ile-X-Leu (positions +1 to +3). The SHB SH2 domain binds multiple autophosphorylation sites on the PDGF β-receptor and phosphorylated FGFR-1 (mainly Y776). The proline-rich pro-4/pro-5 motif of SHB binds the SH3 domains of Src, p85α PI3-kinase, and Eps8 in vitro, and in vivo association between SHB and v-Src/Eps8 was detected by co-immunoprecipitation. Degenerate phosphopeptide library, competing peptides, PDGF receptor Y→F mutants, GST-SH3 pull-down, co-immunoprecipitation Oncogene High 7537362
1996 Overexpression of SHB in NIH3T3 fibroblasts causes apoptosis under low-serum conditions, rescued by PDGF-BB but not IGF-1, indicating SHB can transduce apoptotic signals downstream of specific tyrosine kinase receptors. Stable transfection, TUNEL/pyknotic nuclei staining, serum deprivation, growth factor rescue Oncogene Medium 8806685
1997 SHB overexpression in NIH3T3 cells downregulates Eps8 protein and mRNA, increases basal PI3-kinase activity, and elevates STAT1 expression, demonstrating that SHB modulates expression and activity of SH3 domain-containing signaling proteins. Western blot, Northern blot, in vitro PI3-kinase activity assay, stable transfection Experimental cell research Low 9087167
1998 SHB is expressed in PC12 cells and its overexpression enhances NGF- and bFGF-induced neurite outgrowth in an SH2 domain-dependent manner. An NGF-activated 140-kDa phosphotyrosine protein co-immunoprecipitates with SHB, and SHB tyrosine phosphorylation is greatly enhanced in SHB-overexpressing cells. Stable transfection, neurite outgrowth assay, co-immunoprecipitation, SH2 domain-inactivating mutation (R522K) Cell growth & differentiation Medium 9751119
1998 Upon T cell receptor stimulation in Jurkat cells, SHB associates via its SH2 domain with the TCR ζ-chain (p22), via a PTB domain with p36/38 (Lnk-related protein) in a phosphotyrosine-dependent manner, and via its proline-rich regions with Grb2 SH3 domains. The SHB PTB domain preferentially binds the sequence Asp-Asp-X-pTyr. Overexpression of SH2-inactive SHB (R522K) reduced TCR-stimulated tyrosine phosphorylation of multiple proteins. Co-immunoprecipitation, phosphopeptide library, competing peptides, dominant-negative overexpression Oncogene High 9484780
1999 SHB associates with PLC-γ1 and LAT in Jurkat T cells. Overexpression of SH2-inactive SHB diminishes LAT phosphorylation, MAPK activation, PLC-γ1 phosphorylation, cytoplasmic Ca2+ rise, NFAT activation, and endogenous IL-2 production upon TCR stimulation, placing SHB upstream of LAT/PLC-γ1 in TCR signaling. Co-immunoprecipitation, dominant-negative overexpression, calcium imaging, NFAT reporter assay, cytokine ELISA The Journal of biological chemistry High 10488157
1999 Transgenic overexpression of SHB in pancreatic β-cells increases β-cell area, insulin secretion, and islet DNA content, but also enhances apoptosis under cytokine or streptozotocin stress, demonstrating a dual role for SHB in β-cell growth and death. Rat insulin promoter transgenic mice, glucose tolerance tests, islet isolation, apoptosis assay, streptozotocin treatment Molecular medicine Medium 10404514
2000 Endostatin treatment induces tyrosine phosphorylation of SHB and formation of multiprotein complexes. SHB SH2 domain fusion protein precipitates a 125-kDa phosphotyrosyl protein with intrinsic or associated tyrosine kinase activity from endostatin-treated endothelial cells. Endostatin-induced apoptosis in FGF-2-treated endothelial cells requires both heparin-binding ability of endostatin and a functional SHB SH2 domain. GST-SH2 pull-down, tyrosine phosphorylation assay, in vitro kinase assay, SH2 domain-inactivating mutation, apoptosis assay Blood Medium 10828022
2000 GTK (FRK/RAK) overexpression in PC12 cells induces SHB phosphorylation and association between SHB and FAK, and increases CrkII complex formation with FAK and SHB. GTK-dependent neurite outgrowth involves Rap1 activation, and this pathway is inhibited by RalGDS-RBD or Rap1GAP, placing SHB in a GTK→SHB/FAK→Rap1 signaling cascade. Co-immunoprecipitation, Western blot (phospho-specific), dominant-negative Rap1 pathway inhibitors, neurite outgrowth assay The Journal of biological chemistry Medium 10878015
2000 In PC12-SHB overexpressing cells, NGF and EGF (but not FGF-2) induce Rap1 activation in an SH2 domain-dependent manner. CrkII SH2 domain interacts with SHB and a 130-135-kDa phosphotyrosine protein in PC12-SHB cells. Blocking Rap1 with RalGDS-RBD or Rap1GAP reduces NGF-dependent neurite outgrowth in SHB-overexpressing cells. Rap1 activation assay, co-immunoprecipitation, dominant-negative constructs, neurite outgrowth assay, SH2 domain mutant Experimental cell research Medium 10964504
2000 SHB associates with the PDGF-α receptor via its SH2 domain at tyrosine 720 of the kinase insert domain. Overexpression of wild-type (but not R522K) SHB in PhB fibroblasts decreases PDGF-induced membrane ruffle formation, stimulates filopodia, and diminishes PDGF-induced Rac activation, while PI3-kinase activity and Akt phosphorylation are unaffected. Co-immunoprecipitation, SH2 domain mutant (R522K), Rac activation assay, PI3-kinase assay, cytoskeletal imaging Experimental cell research Medium 10837138
2002 The SHB SH2 domain binds to tyrosine 766 in FGFR-1 via its SH2 domain, leading to SHB phosphorylation. Overexpression of SH2-inactive SHB dramatically reduces FGFR-1-mediated FRS2 phosphorylation and attenuates Ras/MEK/MAPK pathway activation and mitogenicity, establishing SHB as an adaptor linking FGFR-1 Y766 to FRS2 phosphorylation. Chimeric receptor system, Y766F mutation, SH2 domain mutant overexpression, FRS2 phosphorylation assay, MAPK assay, mitogenicity assay Molecular biology of the cell High 12181353
2002 SHB associates with SLP-76, ZAP70, Vav, and Gads in Jurkat T cells. These proteins bind to distinct domains of SHB independently. Overexpression of SH2-inactive SHB reduces SLP-76 and Vav phosphorylation and JNK activation upon TCR stimulation. Upon TCR stimulation, SHB localizes to glycolipid-enriched membrane microdomains (lipid rafts), where it recruits the SLP-76/Gads/Vav complex to the TCR ζ-chain and ZAP70. Co-immunoprecipitation, GST fusion protein domain mapping, dominant-negative overexpression, lipid raft fractionation, JNK activation assay European journal of biochemistry High 12084069
2002 SHB overexpression in IRS-1/2-expressing RINm5F cells and islet cells from SHB-transgenic mice leads to increased basal IRS-1 tyrosine phosphorylation and assembly of a multiprotein complex containing SHB, IRS-1, IRS-2, FAK, and PI3-kinase, resulting in enhanced basal Akt phosphorylation. Co-immunoprecipitation, in vitro kinase assay, Western blot (phospho-specific), transgenic mouse islets Molecular medicine Medium 12520086
2002 SHB associates with the IL-2 receptor β and γ chains via its SH2 domain in a phosphotyrosine-dependent manner, with the main binding site being phosphorylated Tyr-510 in IL-2Rβ. JAK1 and JAK3 associate with SHB via its proline-rich regions. SHB promotes cell survival in the presence of IL-2 in a manner dependent on both a functional SHB SH2 domain and intact Shb-binding tyrosines in IL-2Rβ. Co-immunoprecipitation, GST fusion protein pull-down, IL-2Rβ Y→F mutants, apoptosis assay Biochemical and biophysical research communications Medium 12200137
2003 SHB directly associates with FAK via its PTB domain in brain endothelial cells upon FGF-2 stimulation. SHB overexpression increases FAK phosphorylation and cell spreading on collagen. FGF-2-induced SHB tyrosine phosphorylation is Src-dependent but FAK-independent. Active Src (v-Src) enhances SHB phosphorylation. Co-immunoprecipitation, PTB domain mutant, Src inhibitor, temperature-sensitive v-Src fibroblasts, cell spreading assay Cellular signalling High 12464388
2004 SHB is phosphorylated in a Src-dependent manner upon VEGF stimulation. The SHB SH2 domain binds phosphorylated tyrosine 1175 in the C-terminal tail of VEGFR-2 in a GST pull-down assay, and this interaction was confirmed by co-immunoprecipitation. SHB siRNA knockdown (80%) abrogates VEGF-induced PI3-kinase stimulation, FAK Y576 phosphorylation, focal adhesion formation, stress fiber formation, and cell migration. GST pull-down, co-immunoprecipitation, VEGFR-2 Y1175 mutant, siRNA knockdown, PI3-kinase assay, FAK phosphorylation, migration assay The Journal of biological chemistry High 15026417
2006 SHB interacts with c-Abl via a mechanism involving both c-Abl SH3 and SH2 domains binding to tyrosine-phosphorylated SHB. SHB regulates c-Abl kinase activity. SHB overexpression promotes hydrogen peroxide-induced cell death, and SHB knockdown modulates c-Abl activity and cell death in response to cisplatin and tunicamycin. Co-immunoprecipitation, kinase activity assay, SHB knockdown (siRNA/shRNA), apoptosis assay with genotoxic/ER-stress agents Experimental cell research Medium 17112510
2007 SHB associates with EBV LMP2A through SH2 and PTB domain interactions with phosphorylated tyrosine motifs (including the ITAM motif) in the LMP2A N-terminal tail. shRNA-mediated SHB knockdown abolishes constitutive Akt activation in LMP2A-expressing cells. SHB/LMP2A interaction via the ITAM motif also regulates Syk kinase stability. Co-immunoprecipitation, domain mapping with SH2/PTB mutations, shRNA knockdown, Akt phosphorylation assay Oncogene High 17311000
2007 SHB knockdown in SVR angiosarcoma endothelial cells increases susceptibility to cisplatin and staurosporine-induced apoptosis, reduces FAK phosphorylation at Y576/577, and causes an elongated cell phenotype. In vivo, SHB-knockdown SVR tumors treated with honokiol showed increased apoptosis and strongly reduced tumor growth. Inducible lentiviral shRNA knockdown, apoptosis assay, FAK phosphorylation (Western blot), in vivo tumor growth The Journal of investigative dermatology Medium 17914455
2009 Shb null mice display increased vascular permeability in heart, kidney, and skin under basal conditions but reduced VEGF-stimulated vascular permeability. Shb-deficient endothelial cells show cytoskeletal abnormalities and aberrant ultrastructure (cytoplasmic extensions projecting toward lumen) in liver sinusoids and heart capillaries. Tumor growth was retarded in Shb knockout mice with decreased angiogenesis. Shb knockout mouse, vascular permeability assay, electron microscopy, VE-cadherin immunostaining, Matrigel plug angiogenesis, isolated endothelial cell experiments Cancer research Medium 19223532
2009 Shb knockout mice show elevated basal blood glucose and blunted first-phase insulin secretion during glucose stimulation. Shb-deficient islets have reduced readily releasable granule pools (capacitance measurements), reduced islet microvascular density, and altered islet capillary morphology. Increased Pdx1 expression and reduced VEGF-A expression were observed in freshly isolated Shb-null islets. Shb knockout mouse, pancreas perfusion insulin secretion, patch-clamp capacitance measurements, immunostaining, gene expression (RT-PCR), insulin sensitivity test The Journal of endocrinology Medium 19696098
2010 Loss of Shb in oocytes accelerates oogenesis but impairs follicle maturation. Absence of SHB enhances ERK and RSK signaling and increases ribosomal protein S6 phosphorylation in oocytes. Shb-deficient oocytes show less synchronized meiosis I completion, and Shb-null embryos display impaired early embryo development after in vitro fertilization. Shb knockout mouse, in vitro fertilization, live-cell imaging of meiosis, Western blot (pERK, pRSK, pS6), follicle staging PloS one Medium 20585392
2011 Shb knockout mice show increased basal TCR activation and reduced stimulation-induced phosphorylation in peripheral CD4+ T cells, leading to increased proliferative response and elevated IL-4 production (Th2 skewing), without major changes in thymocyte development. Shb knockout mouse, T cell stimulation assays, phospho-flow cytometry, cytokine ELISA, proliferation assay BMC immunology Medium 21223549
2012 In Shb-deficient lung endothelial cells, VEGF-A stimulation fails to reduce VE-cadherin/VEGFR-2 co-localization at adherens junctions (opposite to wild-type), and VEGF-A-induced ERK, Akt, and Rac1 activation are absent, demonstrating SHB is required for VEGF-A-dependent junctional remodeling and downstream signaling. Isolated lung endothelial cells from Shb knockout mice, spinning-disk confocal and fluorescence microscopy, Rac1 activation assay, Western blot (pERK, pAkt) Cellular signalling Medium 23000345
2012 The LMP2A protein of EBV recruits both Shb and ITSN1 to a complex. Shb simultaneously interacts with phosphorylated tyrosines of LMP2A and SH3 domains of ITSN1, mediating indirect ITSN1-LMP2A interaction. Syk kinase phosphorylates both ITSN1 and Shb in LMP2A-expressing cells, while Shb phosphorylation additionally requires Lyn kinase activity. Co-immunoprecipitation, kinase inhibitors (Syk, Lyn), Western blot (phospho-Shb, phospho-ITSN1) Cellular signalling Medium 22975684
2013 Shb-deficient long-term hematopoietic stem cells (LT-HSCs) show elevated basal activities of FAK/Rac1/p21-activated kinase signaling and reduced responsiveness to Stem Cell Factor. FAK inhibitor treatment increases Shb knockout LT-HSC proliferation, establishing SHB as a negative regulator of FAK in LT-HSC cell cycle control. Shb knockout mouse, bone marrow transplantation, flow cytometry, FAK inhibitor treatment, Western blot (pFAK, pRac1/PAK) Experimental cell research Medium 23528453
2014 Absence of SHB in pancreatic β-cells causes elevated FAK, IRS, and AKT activities under basal conditions, increased β-catenin expression and nuclear localization, and a delayed glucose-induced cAMP rise. FAK inhibition increases submembrane cAMP, implicating elevated FAK activity as the cause of impaired insulin exocytosis in Shb-deficient β-cells. Shb knockout mouse, live-cell cAMP imaging, patch-clamp, FAK inhibitor, Western blot (pFAK, pIRS, pAkt, β-catenin), semi-quantitative PCR The Journal of endocrinology High 25274988
2014 Shb knockout BCR-ABL-transformed bone marrow cells exhibit elevated FAK activity, increased colony formation without cytokines, and accelerated leukemia progression with earlier death in recipients. Transplanting Shb-knockout leukemic cells to Shb-knockout recipients revealed that peripheral blood neutrophilia is niche-dependent, while accelerated cell expansion is cell-intrinsic and FAK-dependent. Retroviral BCR-ABL transformation of knockout bone marrow, transplantation, flow cytometry, Western blot (pFAK), methylcellulose colony assay, qPCR cytokines Journal of hematology & oncology Medium 24952416
2019 VEGFA-induced co-localization between VEGFR2 and SHB occurs within <2.5 min and requires tyrosine 1175 in VEGFR2. SHB then recruits FAK to VEGFR2, as FAK/VEGFR2 co-localization is significantly reduced in SHB-deficient endothelial cells after VEGFA stimulation. Absence of SHB also alters basal focal adhesion distribution to a primarily perinuclear location. TIRF microscopy (live cell), VEGFR2 Y1175F mutant, SHB-deficient primary lung endothelial cells, HEK293 cells Cells High 31847469
2020 SHB is essential for EphB2-mediated heterotypic cell segregation. SHB interacts with Nck via phospho-Tyr297, with RasGAP via phospho-Tyr246, and with α- and β-Chimaerin Rac GAPs via phospho-Tyr336. These SHB complexes are also formed downstream of EphA4, EphA8, and EphB4, indicating a conserved scaffolding function for SHB across multiple Eph receptors in cytoskeletal rearrangement. Co-immunoprecipitation, HEK293 cell segregation assay, Shb tyrosine mutants (Y246, Y297, Y336), multiple Eph receptor constructs The Journal of biological chemistry High 32060095
2020 Conditional inactivation of Shb in pericytes (Pdgfrb-CreERT2) decreases pericyte coverage of small tumor vessels, increases vascular leakage, and elevates lung metastasis of B16F10 melanoma, with aberrant PDGFRB signaling. Endothelial-specific Shb deletion (Cdh5-CreERT2) reduces tumor growth and vascular leakage but does not affect pericyte coverage or metastasis. Conditional Cre-lox knockout (cell-type specific), tumor metastasis assay, flow cytometry, vascular permeability assay, RNAseq International journal of cancer Medium 32441314

Source papers

Stage 0 corpus · 67 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 242 10828022
2004 The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. The Journal of biological chemistry 205 15026417
2002 The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells. Molecular biology of the cell 76 12181353
1994 Shb is a ubiquitously expressed Src homology 2 protein. Oncogene 66 8302579
1995 Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins. Oncogene 57 7537362
1998 Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins. Oncogene 52 9484780
2003 The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. Current molecular medicine 51 12776987
1999 Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells. The Journal of biological chemistry 35 10488157
1989 Properties of ShB A-type potassium channels expressed in Shaker mutant Drosophila by germline transformation. Neuron 34 2484347
2000 GTK, a Src-related tyrosine kinase, induces nerve growth factor-independent neurite outgrowth in PC12 cells through activation of the Rap1 pathway. Relationship to Shb tyrosine phosphorylation and elevated levels of focal adhesion kinase. The Journal of biological chemistry 33 10878015
2009 Dysfunctional microvasculature as a consequence of shb gene inactivation causes impaired tumor growth. Cancer research 30 19223532
1996 Apoptosis of NIH3T3 cells overexpressing the Src homology 2 domain protein Shb. Oncogene 30 8806685
2000 Shf, a Shb-like adapter protein, is involved in PDGF-alpha-receptor regulation of apoptosis. Biochemical and biophysical research communications 29 11095946
2003 The Shb adaptor protein causes Src-dependent cell spreading and activation of focal adhesion kinase in murine brain endothelial cells. Cellular signalling 28 12464388
1999 Transgenic mice expressing Shb adaptor protein under the control of rat insulin promoter exhibit altered viability of pancreatic islet cells. Molecular medicine (Cambridge, Mass.) 27 10404514
2007 Shb null allele is inherited with a transmission ratio distortion and causes reduced viability in utero. Developmental dynamics : an official publication of the American Association of Anatomists 26 17676633
2000 NGF-Dependent neurite outgrowth in PC12 cells overexpressing the Src homology 2-domain protein shb requires activation of the Rap1 pathway. Experimental cell research 26 10964504
2000 Platelet-derived growth factor-mediated signaling through the Shb adaptor protein: effects on cytoskeletal organization. Experimental cell research 22 10837138
2002 Role of the Src homology 2 domain-containing protein Shb in murine brain endothelial cell proliferation and differentiation. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 21 11959815
1998 The Src homology 2 domain protein Shb transmits basic fibroblast growth factor- and nerve growth factor-dependent differentiation signals in PC12 cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 20 9751119
2011 Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells. BMC immunology 19 21223549
2002 Dual role of the tyrosine kinase GTK and the adaptor protein SHB in beta-cell growth: enhanced beta-cell replication after 60% pancreatectomy and increased sensitivity to streptozotocin. The Journal of endocrinology 19 11786382
2002 Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells. European journal of biochemistry 19 12084069
2010 The Src homology 2 domain-containing adapter protein B (SHB) regulates mouse oocyte maturation. PloS one 18 20585392
2015 Vascular dysfunction and increased metastasis of B16F10 melanomas in Shb deficient mice as compared with their wild type counterparts. BMC cancer 17 25885274
2012 Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice: implications for tumor angiogenesis. Molecular oncology 17 22336752
2012 Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency. Angiogenesis 17 22562363
2007 The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein-Barr virus LMP2A membrane protein. Oncogene 16 17311000
2005 Shb promotes blood vessel formation in embryoid bodies by augmenting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-beta signaling. Experimental cell research 16 15919073
2002 IL-2 receptor signaling through the Shb adapter protein in T and NK cells. Biochemical and biophysical research communications 16 12200137
2019 Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB. Cells 15 31847469
2012 Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells. Cellular signalling 15 23000345
2006 Consequences of Shb and c-Abl interactions for cell death in response to various stress stimuli. Experimental cell research 15 17112510
2002 Overexpression of the Shb SH2 domain-protein in insulin-producing cells leads to altered signaling through the IRS-1 and IRS-2 proteins. Molecular medicine (Cambridge, Mass.) 15 12520086
2013 The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity. Experimental cell research 14 23528453
2012 The LMP2A protein of Epstein-Barr virus regulates phosphorylation of ITSN1 and Shb adaptors by tyrosine kinases. Cellular signalling 14 22975684
2009 Increased Hsp70 expression attenuates cytokine-induced cell death in islets of Langerhans from Shb knockout mice. Biochemical and biophysical research communications 14 19615333
2007 Shb gene knockdown increases the susceptibility of SVR endothelial tumor cells to apoptotic stimuli in vitro and in vivo. The Journal of investigative dermatology 14 17914455
2003 The SHB adapter protein is required for efficient multilineage differentiation of mouse embryonic stem cells. Experimental cell research 13 12729793
2019 The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors. Scientific reports 12 31101877
2014 The Src homology-2 protein Shb modulates focal adhesion kinase signaling in a BCR-ABL myeloproliferative disorder causing accelerated progression of disease. Journal of hematology & oncology 12 24952416
2006 The SHB adapter protein is required for normal maturation of mesoderm during in vitro differentiation of embryonic stem cells. The Journal of biological chemistry 12 16971391
2015 Shb deficiency in endothelium but not in leucocytes is responsible for impaired vascular performance during hindlimb ischaemia. Acta physiologica (Oxford, England) 11 25561022
2014 Absence of the adaptor protein Shb potentiates the T helper type 2 response in a mouse model of atopic dermatitis. Immunology 11 24645804
2009 Impaired glucose homeostasis in Shb-/- mice. The Journal of endocrinology 11 19696098
2015 The role of the Src Homology-2 domain containing protein B (SHB) in β cells. Journal of molecular endocrinology 10 26489764
2007 Interdependent fibroblast growth factor and activin A signaling promotes the expression of endodermal genes in differentiating mouse embryonic stem cells expressing Src Homology 2-domain inactive Shb. Differentiation; research in biological diversity 10 18093225
1995 Association of Hb S/Hb lepore and delta beta-thalassemia/Hb lepore in Sicilian patients: review of the presence of Hb lepore in Sicily. European journal of haematology 10 7543057
2020 Pericyte dysfunction due to Shb gene deficiency increases B16F10 melanoma lung metastasis. International journal of cancer 9 32441314
2021 Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis. International journal of molecular sciences 8 34768912
1998 Compound heterozygosity Hb S/Hb Hope (beta 136 Gly-->Asp): a pitfall in the newborn screening for sickle cell disease. Journal of medical screening 8 9575456
2020 The Shb scaffold binds the Nck adaptor protein, p120 RasGAP, and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2. The Journal of biological chemistry 7 32060095
2018 Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas. Oncotarget 7 29721156
2017 Hexavalent Chromium Reduction from Pollutant Samples by Achromobacter xylosoxidans SHB 204 and its Kinetics Study. Indian journal of microbiology 7 28904413
2006 SHB and angiogenic factors promote ES cell differentiation to insulin-producing cells. Biochemical and biophysical research communications 7 16630561
2007 Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein. BMC cancer 6 17697368
1997 Hb S/Hb Lepore with mild sickling symptoms: a hemoglobin variant with mostly delta-chain sequences ameliorates sickle-cell disease. American journal of hematology 6 9034293
1997 Modulation of Src homology 3 proteins by the proline-rich adaptor protein Shb. Experimental cell research 6 9087167
2018 Disparate effects of Shb gene deficiency on disease characteristics in murine models of myeloid, B-cell, and T-cell leukemia. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 4 29792386
2022 Sulfhemoglobin under the spotlight - Detection and characterization of SHb and HbFeIII-SH. Biochimica et biophysica acta. Molecular cell research 3 36220452
2014 Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets. The Journal of endocrinology 3 25274988
2022 Profiling of 35 Cases of Hb S/Hb E (HBB: c.20A>T/HBB: c.79G>a), Disease and Association with α-Thalassemia and β-Globin Gene Cluster Haplotypes from Odisha, India. Hemoglobin 2 35243949
2017 Evaluation and validation of commercial antibodies for the detection of Shb. PloS one 2 29194461
1990 Unusual sickle cell disease observed for the first time in Italy: Hb S-Hb D Los Angeles. Haematologica 2 2097263
2006 The role of the adapter protein SHB in embryonic stem cell differentiation into the pancreatic beta-cell and endothelial lineages. Methods in molecular biology (Clifton, N.J.) 1 16846036
2023 Functional characterization of compound heterozygosity Hb S/Hb Deer Lodge in Brazil. Hematology, transfusion and cell therapy 0 38307823
2020 Absence of the Shb gene in mixed-lineage leukemia MLL-AF9 cells increases latency in mice despite higher proliferation rates in vitro. Experimental cell research 0 33220260

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