Affinage

SHB

SH2 domain-containing adapter protein B · UniProt Q15464

Length
509 aa
Mass
55.0 kDa
Annotated
2026-04-28
67 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHB is a multi-domain scaffold/adaptor protein that couples diverse receptor tyrosine kinases to downstream signaling cascades controlling cell survival, migration, cytoskeletal remodeling, and exocytosis. Its SH2 domain docks onto phosphotyrosine residues of VEGFR-2 (Y1175), FGFR-1 (Y766), PDGFR-α (Y720), IL-2Rβ (Y510), TCR ζ-chain, and Eph receptors, while its PTB domain binds FAK and its proline-rich motifs recruit SH3-containing partners including Src, PI3K p85α, Grb2, and JAK1/3, thereby assembling context-dependent multiprotein complexes that activate PI3K/Akt, Rac1, Rap1, MAPK, and FAK pathways (PMID:7537362, PMID:15026417, PMID:9484780, PMID:12464388, PMID:32060095). In vivo, Shb knockout mice exhibit defective VEGF-induced vascular permeability, impaired angiogenesis and tumor growth, reduced hematopoietic stem cell proliferation due to constitutively elevated FAK signaling, blunted first-phase insulin secretion from pancreatic β-cells, and skewed T-cell Th1/Th2 balance (PMID:19223532, PMID:23528453, PMID:25274988, PMID:19696098, PMID:21223549). SHB phosphorylation at specific tyrosines (Y246, Y297, Y336) further dictates effector recruitment — for example recruiting Nck and chimaerin Rac GAPs downstream of EphB2 to drive cell boundary formation — establishing SHB as a phosphotyrosine-dependent signaling hub whose complex composition determines cellular output (PMID:32060095, PMID:32441314).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Identification of SHB as a novel SH2-domain adaptor that selectively binds the autophosphorylated PDGF β-receptor established it as a new class of signaling scaffold linking RTKs to SH3-domain effectors.

    Evidence GST-SH2 pulldown, Western blot, cDNA cloning in fibroblasts

    PMID:8302579

    Open questions at the time
    • No downstream signaling consequence demonstrated
    • Endogenous expression pattern not yet defined
  2. 1995 High

    Mapping the SH2 binding specificity (pY-T/V/I-X-L) and showing proline-rich motifs recruit Src, PI3K p85α, and Eps8 SH3 domains defined the modular logic by which SHB assembles multiprotein complexes.

    Evidence Degenerate phosphopeptide library, PDGFR Y→F mutants, GST-SH3 pulldowns, co-immunoprecipitation

    PMID:7537362

    Open questions at the time
    • In vivo relevance of individual SH3 interactions not tested
    • PTB domain function not yet characterized
  3. 1996 Medium

    Demonstration that SHB overexpression induces apoptosis rescued by PDGF-BB but not IGF-1 provided the first evidence that SHB transduces receptor-specific survival/death signals.

    Evidence Stable NIH3T3 overexpression, TUNEL assay, growth factor rescue

    PMID:8806685

    Open questions at the time
    • Overexpression artifact possible
    • Mechanism of apoptosis induction not defined
  4. 1998 High

    Discovery of SHB engagement with TCR ζ-chain via SH2, Grb2 via proline-rich motifs, and a novel PTB domain (binding Asp-Asp-X-pTyr) expanded SHB's receptor repertoire beyond RTKs to immune receptor signaling.

    Evidence Co-IP in Jurkat cells, phosphopeptide library for PTB, dominant-negative R522K mutant

    PMID:9484780

    Open questions at the time
    • Identity of 36/38 kDa PTB-binding partner uncertain
    • Physiological T-cell phenotype not yet tested in vivo
  5. 1999 High

    Linking SHB to PLC-γ1, LAT phosphorylation, calcium flux, MAPK, and NFAT/IL-2 production downstream of TCR positioned SHB as a proximal organizer of T-cell activation signaling.

    Evidence Dominant-negative SHB in Jurkat cells, calcium imaging, NFAT reporter, IL-2 ELISA

    PMID:10488157

    Open questions at the time
    • No loss-of-function in primary T cells yet
    • Mechanism of LAT phosphorylation regulation unclear
  6. 2000 Medium

    Multiple studies converged to show SHB regulates small GTPases Rac1 and Rap1 downstream of PDGFR, FGFR, and TrkA, controlling cytoskeletal organization, neurite outgrowth, and cell morphology — establishing Rac/Rap as core SHB effector axes.

    Evidence Rac1/Rap1 activity pulldowns, CrkII co-IP, PDGFR Y→F mutants, dominant-negative Rap1 approaches in NIH3T3, PC12, and IBE cells

    PMID:10837138 PMID:10878015 PMID:10964504

    Open questions at the time
    • Direct versus indirect regulation of GTPases not resolved
    • Endogenous SHB loss-of-function not tested
  7. 2002 High

    SHB was shown to scaffold SLP-76, Vav, Gads, and ZAP70 at TCR lipid rafts, and separately to nucleate IRS-1/IRS-2/FAK/PI3K complexes in β-cells, demonstrating how SHB's multiple domains build tissue-specific signaling platforms.

    Evidence Co-IP domain mapping and lipid raft fractionation in Jurkat cells; co-IP and Akt phosphorylation in RINm5F β-cells

    PMID:12084069 PMID:12520086

    Open questions at the time
    • Stoichiometry and dynamics of multiprotein complexes unknown
    • Structural basis for simultaneous multi-partner engagement absent
  8. 2002 High

    Mapping SHB SH2 domain binding to FGFR-1 Y766 and showing dominant-negative SHB blocks FRS2 phosphorylation and MAPK-dependent proliferation placed SHB as an intermediary between FGFR-1 and the Ras/MAPK cascade.

    Evidence Chimeric receptor with Y766F mutation, GST-SH2 pulldown, proliferation assay

    PMID:12181353

    Open questions at the time
    • Whether SHB directly activates FRS2 or acts through a kinase intermediate not resolved
  9. 2003 High

    Identification of the PTB domain as the FAK-binding module and Src as the kinase phosphorylating SHB established the FAK–SHB–Src signaling node that recurs across many SHB functions.

    Evidence PTB domain fusion pulldown, temperature-sensitive v-Src cells, Src inhibitor, FAK phosphorylation blots

    PMID:12464388

    Open questions at the time
    • Direct binding interface between PTB and FAK not structurally defined
  10. 2004 High

    Demonstrating that SHB SH2 domain docks on VEGFR-2 Y1175 and that SHB knockdown abolishes VEGF-induced PI3K, FAK phosphorylation, and endothelial migration established SHB as a critical mediator of VEGF signaling.

    Evidence GST-SH2 pulldown with VEGFR-2 peptides, siRNA in endothelial cells, PI3K assay, FAK/migration readouts

    PMID:15026417

    Open questions at the time
    • In vivo vascular consequence not yet shown at this point
  11. 2009 High

    Shb knockout mice revealed that loss of SHB causes dysfunctional endothelial ultrastructure, increased baseline vascular permeability, reduced VEGF-stimulated permeability, and impaired tumor angiogenesis — providing the first in vivo validation of SHB's vascular functions.

    Evidence Shb global knockout, electron microscopy, vascular permeability assays, tumor implantation

    PMID:19223532

    Open questions at the time
    • Endothelial-specific versus systemic contributions not separated
  12. 2009 High

    Patch-clamp capacitance measurements in Shb-null islets showed dramatically reduced readily releasable insulin granules despite normal Ca2+ handling, pinpointing SHB's role to the exocytotic machinery rather than stimulus-secretion coupling upstream of Ca2+.

    Evidence Patch-clamp electrophysiology, pancreatic perfusion, islet vascular imaging in knockout mice

    PMID:19696098

    Open questions at the time
    • Molecular target in exocytotic machinery not identified
    • Relative contribution of vascular versus β-cell-intrinsic defects unclear
  13. 2013 Medium

    Finding that Shb-null LT-HSCs have constitutively elevated FAK/Rac1/PAK signaling and that FAK inhibition rescues their proliferation defect established SHB as a negative regulator of FAK in hematopoietic stem cells.

    Evidence Flow cytometry of bone marrow, competitive transplantation, FAK/Rac1 Western blots, FAK inhibitor rescue in knockout

    PMID:23528453

    Open questions at the time
    • Mechanism by which SHB restrains FAK activity not defined
    • Whether this applies to all stem cell contexts unknown
  14. 2014 High

    Live-cell cAMP FRET imaging showed that chronically elevated FAK in Shb-null β-cells delays glucose-induced sub-membrane cAMP rise, causally linking FAK hyperactivation to the insulin secretion defect and resolving the downstream mechanism.

    Evidence cAMP FRET biosensor, patch-clamp, FAK inhibitor rescue in Shb-knockout islets

    PMID:25274988

    Open questions at the time
    • How FAK suppresses cAMP generation molecularly is unknown
    • Whether FAK inhibition fully rescues secretion in vivo not tested
  15. 2019 High

    TIRF microscopy resolved the temporal sequence of VEGFR2–SHB–FAK co-localization at the plasma membrane (<2.5 min) and showed SHB is required for VEGFR2-dependent FAK recruitment to focal adhesions, providing the real-time spatial mechanism.

    Evidence TIRF live-cell imaging, Y1175F-VEGFR2 mutant, SHB-knockout primary endothelial cells

    PMID:31847469

    Open questions at the time
    • Whether SHB directly bridges VEGFR2 and FAK or acts through intermediaries not resolved at the molecular level
  16. 2020 High

    Identification of SHB phosphotyrosines Y246, Y297, and Y336 as docking sites for Nck, RasGAP, and chimaerin Rac GAPs downstream of EphB2 revealed how SHB's own phosphorylation pattern encodes effector specificity for Eph-mediated cell segregation.

    Evidence Phosphospecific Y→F mutagenesis, mass spectrometry interactome, HEK293 cell segregation assay with multiple Eph receptors

    PMID:32060095

    Open questions at the time
    • Structural basis for multi-site phosphorylation decoding unknown
    • In vivo Eph boundary phenotype in Shb knockout not tested
  17. 2020 High

    Cell-type-specific conditional knockouts separated endothelial SHB (controls vascular leakage and tumor angiogenesis) from pericyte SHB (controls pericyte coverage and metastatic dissemination), demonstrating compartmentalized functions within the vascular niche.

    Evidence Cdh5-CreERt2 and Pdgfrb-CreERt2 conditional Shb knockouts, tumor implantation, RNAseq, vascular permeability

    PMID:32441314

    Open questions at the time
    • Downstream signaling pathways in pericytes not deeply characterized
    • Therapeutic relevance of targeting SHB in specific vascular compartments not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for simultaneous multi-domain engagement of distinct partners, the mechanism by which SHB restrains FAK kinase activity, and whether SHB phosphorylation codes are conserved across receptor contexts in vivo.
  • No crystal or cryo-EM structure of SHB or its complexes
  • No systematic in vivo phosphosite mutant analysis across tissues
  • Mechanism by which SHB suppresses basal FAK activity remains undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 8
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3
Partners
C-ABLFAKFGFR1NCKPI3KSLP76VAV1VEGFR2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 SHB was identified as a novel SH2 domain-containing adaptor protein with proline-rich domains; its SH2 domain fusion protein binds the autophosphorylated PDGF β-receptor but not the EGF receptor, establishing SHB as a signal transduction adaptor linking SH3 domain proteins to tyrosine kinase receptors. GST-SH2 fusion protein pulldown, Western blot, cDNA cloning and transient/stable transfection Oncogene High 8302579
1995 The SHB SH2 domain preferentially binds the phosphopeptide motif pTyr-Thr/Val/Ile-X-Leu; it binds multiple autophosphorylation sites on the PDGF β-receptor and phosphorylated FGFR-1 (mainly via Y776); the proline-rich motifs (pro-4/pro-5) bind Src, p85α PI3-kinase, and Eps8 SH3 domains in vitro, and in vivo association with v-Src and Eps8 was confirmed by co-immunoprecipitation. Degenerate phosphopeptide library screening, competing peptides with PDGF receptor Y→F mutants, GST-SH3 fusion protein pulldowns, co-immunoprecipitation Oncogene High 7537362
1996 Overexpression of SHB in NIH3T3 fibroblasts causes apoptosis (pyknotic nuclei by TUNEL) under low-serum conditions, which is rescued by PDGF-BB but not IGF-1, establishing SHB as a mediator of apoptotic signaling downstream of specific tyrosine kinase receptors. Stable transfection, TUNEL staining, cell counting, PDGF/IGF-1 rescue experiments Oncogene Medium 8806685
1997 SHB overexpression in NIH3T3 cells downregulates Eps8 protein and mRNA, increases basal PI3-kinase activity, and elevates STAT1 mRNA and protein levels, indicating that SHB modulates expression and activity of SH3 domain signaling proteins. Western blot, Northern blot, in vitro PI3-kinase assay in SHB-overexpressing cells Experimental cell research Medium 9087167
1998 SHB is expressed in Jurkat T cells and, upon TCR stimulation, forms multiprotein complexes: Grb2 binds SHB proline-rich motifs via its SH3 domains; the SHB SH2 domain associates with the TCR ζ-chain (p22); a central PTB domain (preferring Asp-Asp-X-pTyr) binds p36/38 (possibly Lnk); overexpression of SHB increases basal phosphorylation of associated proteins, and the R522K SH2-inactive mutant reduces CD3-stimulated tyrosine phosphorylation. Co-immunoprecipitation, phosphopeptide library, dominant-negative mutant overexpression, Western blot Oncogene High 9484780
1998 SHB overexpression in PC12 cells enhances NGF- and bFGF-induced neurite outgrowth in an SH2 domain-dependent manner; SHB is tyrosine phosphorylated and co-immunoprecipitates with a 140 kDa phosphotyrosine protein upon NGF treatment, placing SHB downstream of TrkA/FGFR in neuronal differentiation signaling. Stable transfection, neurite outgrowth assay, immunoprecipitation, Western blot Cell growth & differentiation Medium 9751119
1999 SHB associates with PLC-γ1 in Jurkat T cells; expression of SH2-defective SHB diminishes LAT phosphorylation, blocks PLC-γ1 phosphorylation, abolishes calcium rise, suppresses MAPK activation, prevents NFAT activation, and reduces endogenous IL-2 production upon TCR stimulation. Co-immunoprecipitation, dominant-negative overexpression, calcium imaging, NFAT reporter assay, cytokine ELISA The Journal of biological chemistry High 10488157
1999 Transgenic mice overexpressing SHB in β-cells (under rat insulin promoter) show increased β-cell area, enhanced glucose-stimulated insulin secretion, higher islet DNA content, and elevated apoptosis under cytokine or low-serum stress, establishing a dual role for SHB in β-cell proliferation and death. Transgenic mouse generation, glucose tolerance test, islet isolation, insulin secretion assay, TUNEL staining Molecular medicine Medium 10404514
2000 Endostatin induces tyrosine phosphorylation of SHB and formation of multiprotein complexes in endothelial cells; the SHB SH2 domain pull-down co-precipitates a 125 kDa phosphotyrosyl protein with intrinsic or associated tyrosine kinase activity; SHB overexpression in IBE cells enhances endostatin-induced apoptosis in an SH2 domain- and endostatin heparin-binding-dependent manner. Western blot for pTyr-SHB, SH2 domain fusion protein pulldown, overexpression with SH2 mutant, apoptosis assays Blood High 10828022
2000 GTK (FRK/RAK) overexpression in PC12 cells causes increased FAK content, phosphorylation of SHB, and association between SHB and FAK; this correlates with CrkII complex formation with p130Cas, FAK and SHB, and Rap1 activation required for neurite outgrowth, placing SHB downstream of GTK in a FAK/CrkII/Rap1 pathway. Western blot, co-immunoprecipitation, Rap1 activity assay (RalGDS-RBD pulldown), dominant-negative transfection, neurite outgrowth assay The Journal of biological chemistry Medium 10878015
2000 SHB overexpression in PC12 cells enables NGF- and EGF- (but not FGF-2-) induced Rap1 activation in an SH2 domain-dependent manner; CrkII SH2 domain interacts with SHB and a 130-135 kDa phosphotyrosine protein; blocking Rap1 signaling (RalGDS-RBD or Rap1GAP) reduces SHB-dependent neurite outgrowth. Rap1 activity assay, co-immunoprecipitation, dominant-negative transfection, neurite outgrowth assay Experimental cell research Medium 10964504
2000 SHB binds the PDGF-α receptor via its SH2 domain at tyrosine 720 in the kinase insert domain; wild-type SHB overexpression (but not R522K mutant) reduces PDGF-induced membrane ruffle formation, stimulates filopodia, and diminishes Rac activation, indicating SHB regulates PDGF-dependent cytoskeletal organization through Rac. Co-immunoprecipitation, PDGF receptor Y→F mutants, overexpression of WT vs. R522K SHB, Rac activation assay, morphological analysis Experimental cell research Medium 10837138
2002 The SHB SH2 domain binds FGFR-1 at tyrosine 766; overexpression of SH2-inactive SHB (R522K) dramatically reduces FGFR-1-mediated FRS2 phosphorylation and attenuates Ras/MEK/MAPK pathway activation and cell proliferation, placing SHB between FGFR-1 pY766 and FRS2 in mitogenic signaling. Chimeric receptor expression, Y766F mutation, GST-SH2 pulldown, dominant-negative overexpression, FRS2/MAPK Western blot, thymidine incorporation proliferation assay Molecular biology of the cell High 12181353
2002 SHB links SLP-76, Gads, Vav, and ZAP70 with the TCR/CD3 complex in Jurkat T cells; SLP-76 and ZAP70 co-immunoprecipitate with SHB; SHB and Vav co-immunoprecipitate when co-transfected in COS cells; different domains of SHB independently bind SLP-76, Gads, and Vav; SH2-defective SHB reduces SLP-76/Vav phosphorylation and JNK activation; SHB localizes to lipid rafts/GEMs upon TCR stimulation. Co-immunoprecipitation, GST fusion protein pulldowns, dominant-negative overexpression, JNK kinase assay, lipid raft fractionation European journal of biochemistry High 12084069
2002 SHB overexpression in RINm5F β-cells and primary islets increases basal IRS-1 tyrosine phosphorylation and assembles a multiunit complex containing SHB, IRS-1, IRS-2, FAK, and PI3K, leading to enhanced basal Akt phosphorylation and increased cell proliferation. Stable transfection, immunoprecipitation, in vitro kinase assay, Western blot for pAkt, flow cytometry for proliferation Molecular medicine Medium 12520086
2002 SHB overexpression in murine brain endothelial cells (IBE) increases apoptosis on serum withdrawal; both WT and R522K SHB induce spreading and cytoskeletal rearrangements via altered Rac1/Rap1 activation independent of PI3K but dependent on Src family kinases; SH2-mutant SHB (R522K) impairs FGF-2-induced tubular morphogenesis in collagen gels. Stable overexpression, Rac1/Rap1 activation assays, PI3K inhibitor treatment, Src inhibitor treatment, 3D collagen gel morphogenesis assay Cell growth & differentiation Medium 11959815
2002 IL-2 receptor β and γ subunits co-immunoprecipitate with SHB; the SHB SH2 domain binds phosphorylated Tyr-510 on IL-2Rβ; JAK1 and JAK3 associate with SHB proline-rich regions; SHB with functional SH2 domain promotes survival (reduced apoptosis) in the presence of IL-2, while SH2-mutant SHB or Y392F/Y510F IL-2Rβ mutant abrogates this effect. Co-immunoprecipitation in COS cells and primary T/NK cells, GST fusion protein binding, dominant-negative overexpression, apoptosis assay Biochemical and biophysical research communications Medium 12200137
2003 FGF-2 stimulation induces direct association between SHB and FAK mediated by the SHB PTB domain; SHB overexpression (WT or R522K) increases FAK phosphorylation and cell spreading on collagen; SHB tyrosine phosphorylation upon FGF-2 is Src-dependent but FAK-independent; active Src (tsLA29 v-Src) enhances SHB phosphorylation. Co-immunoprecipitation, PTB domain fusion pulldown, temperature-sensitive v-Src cells, Src inhibitor treatment, Western blot for FAK phosphorylation, spreading assay Cellular signalling High 12464388
2004 SHB binds tyrosine 1175 in VEGFR-2 via its SH2 domain; SHB is phosphorylated in a Src-dependent manner upon VEGF stimulation; reduced SHB expression (siRNA) abolishes VEGF-induced PI3K stimulation, FAK phosphorylation at Y576, focal adhesion formation, stress fiber formation, and cell migration. GST-SH2 domain pulldown with VEGFR-2 peptides, co-immunoprecipitation, siRNA knockdown, PI3K assay, FAK/stress fiber immunofluorescence, migration assay The Journal of biological chemistry High 15026417
2005 SHB overexpression in embryonic stem cells promotes vascular structure outgrowth in embryoid bodies, increases VEGFR-2-positive cell numbers and PDGFR-β expression; SH2-mutant SHB (R522K) fails to support vascular structure formation, indicating SHB transduces VEGFR-2 and PDGFR-β signals for vascular differentiation. Stable ES cell transfection, embryoid body differentiation, CD31/VEGFR-2 immunostaining, real-time RT-PCR, PDGF-BB signaling inhibition, microarray Experimental cell research Medium 15919073
2006 SHB-/- embryoid bodies exhibit delayed down-regulation of Brachyury and reduced expression of hematopoietic, vascular, and cardiac lineage markers; SHB-/- ES cells form fewer blood cell colonies and show impaired blood vessel formation after VEGF stimulation, establishing SHB as required for mesoderm-to-hematopoietic/vascular differentiation. SHB knockout ES cell lines, embryoid body differentiation, gene expression by real-time RT-PCR, CD31 immunostaining, methylcellulose hematopoietic colony assay The Journal of biological chemistry Medium 16971391
2006 SHB interacts with c-Abl; tyrosine-phosphorylated SHB recruits c-Abl via concerted SH3 and SH2 domain interactions; SHB regulates c-Abl kinase activity; SHB/c-Abl interaction promotes hydrogen peroxide-induced cell death; SHB knockdown reduces c-Abl activity and alters cell death in response to cisplatin and tunicamycin. Co-immunoprecipitation, c-Abl kinase activity assay, overexpression, lentiviral shRNA knockdown, apoptosis assays Experimental cell research Medium 17112510
2007 SHB associates with the EBV LMP2A N-terminal tail through both SH2 and PTB domain interactions with phosphorylated tyrosine motifs; shRNA-mediated SHB knockdown abolishes constitutive Akt activation in LMP2A-expressing cells; SHB-mediated binding to the LMP2A ITAM motif regulates Syk tyrosine kinase stability. Co-immunoprecipitation, domain-specific binding assays, shRNA knockdown, Western blot for pAkt and Syk Oncogene Medium 17311000
2007 SHB knockdown in SVR angiosarcoma endothelial cells increases susceptibility to cisplatin and staurosporine-induced apoptosis and reduces FAK phosphorylation at Y576/577, coinciding with an elongated cell phenotype; SHB knockdown cells show increased apoptosis and strongly reduced tumor growth in vivo upon honokiol treatment. Inducible lentiviral shRNA knockdown, Western blot for FAK phosphorylation, apoptosis assays, in vivo tumor growth The Journal of investigative dermatology Medium 17914455
2009 Shb knockout mice display dysfunctional endothelial ultrastructure (abnormal cytoplasmic extensions in liver sinusoids/heart capillaries), less distinct VE-cadherin staining, increased baseline vascular permeability in heart/kidney/skin, reduced VEGF-stimulated vascular permeability, and impaired tumor angiogenesis with retarded tumor growth. Shb knockout mouse, electron microscopy of endothelium, VE-cadherin immunostaining, vascular permeability assays, Matrigel plug angiogenesis, tumor implantation Cancer research High 19223532
2009 Shb-/- islets display blunted first-phase glucose-induced insulin secretion with dramatically reduced readily releasable granules (capacitance measurements), altered microvascular morphology with reduced islet capillary density, and elevated basal blood glucose; glucose-induced ATP generation and cytoplasmic Ca2+ are unaffected, implicating SHB in regulation of the exocytotic machinery. Pancreatic perfusion, patch-clamp capacitance measurements, Laser-Doppler blood flow, immunofluorescence of islet vasculature, glucose/insulin tolerance tests The Journal of endocrinology High 19696098
2010 SHB deficiency in mouse oocytes accelerates oogenesis, impairs follicle maturation, causes less synchronized meiosis I completion with premature polar body extrusion in some oocytes, impairs early embryo development after in vitro fertilization, and is associated with enhanced ERK and RSK signaling and increased ribosomal S6 phosphorylation in oocytes. Shb knockout mouse, oocyte staging, polar body extrusion assay, in vitro fertilization, Western blot for pERK/pRSK/pS6 in oocytes PloS one Medium 20585392
2011 Shb knockout T cells display increased basal TCR activation and reduced stimulation-induced phosphorylation, resulting in augmented peripheral CD4+ Th2 proliferation and elevated IL-4 production, establishing SHB as a modulator of TCR signal strength that controls Th1/Th2 balance. Shb knockout mouse, flow cytometry for T cell populations, TCR stimulation assays, intracellular cytokine staining, proliferation assay BMC immunology Medium 21223549
2012 VEGF-A stimulation of wild-type endothelial cells causes dissociation of VE-cadherin from adherens junctions and decreases VE-cadherin/VEGFR-2 co-localization; in SHB-deficient endothelial cells, this response is absent and VEGFA fails to stimulate ERK, Akt, and Rac1, indicating SHB is required for proper VEGFR-2-to-VE-cadherin signaling that controls vascular permeability. Confocal and spinning-disk microscopy co-localization, SHB knockout primary lung endothelial cells, scratch wound assay, Western blot for pERK/pAkt, Rac1 pull-down assay Cellular signalling Medium 23000345
2012 SHB knockout mice exhibit structural vascular abnormalities (increased arteriole frequency, irregular vasculature with fewer branch points and increased tortuosity in cremaster muscle, increased blood flow velocity) and functional defects: VEGF-A does not provoke VE-cadherin dissociation from adherens junctions, and reduced angiogenesis and vascular permeability impairs blood flow recovery after arterial ligation. Micro-CT angiography, intravital microscopy of cremaster, Matrigel plug assay, VE-cadherin immunostaining, femoral artery ligation with Laser-Doppler Angiogenesis Medium 22562363
2012 LMP2A phosphorylation promotes Shb and ITSN1 interaction: Shb simultaneously binds phosphorylated LMP2A tyrosines and ITSN1 SH3 domains, mediating indirect LMP2A-ITSN1 association; Syk kinase phosphorylates both ITSN1 and Shb in LMP2A-expressing cells, while Lyn additionally contributes to Shb phosphorylation. Co-immunoprecipitation, kinase inhibitor experiments (Syk, Lyn), Western blot for phosphoproteins Cellular signalling Medium 22975684
2013 SHB-deficient bone marrow contains fewer long-term hematopoietic stem cells (LT-HSCs) with lower proliferation rates; SHB knockout LT-HSCs exhibit elevated basal FAK/Rac1/PAK signaling and reduced responsiveness to Stem Cell Factor; FAK inhibitor treatment rescues LT-HSC proliferation in knockout mice, establishing SHB as a negative regulator of FAK activity controlling LT-HSC cell cycle. Flow cytometry of bone marrow populations, competitive transplantation, Western blot for FAK/Rac1/PAK, FAK inhibitor treatment, proliferation BrdU assay Experimental cell research Medium 23528453
2014 SHB deficiency in β-cells causes chronically elevated FAK activity, which delays glucose-induced cAMP rise (measured by live-cell FRET imaging of sub-membrane cAMP) and impairs insulin exocytosis; FAK inhibition increases sub-membrane cAMP, directly implicating elevated FAK in the secretory defect. Live-cell cAMP FRET imaging, patch-clamp capacitance measurements, immunoblotting, qPCR, FAK inhibitor treatment in Shb-knockout islets The Journal of endocrinology High 25274988
2014 SHB knockout accelerates BCR-ABL-induced myeloproliferative leukemia due to elevated FAK activity in transformed bone marrow cells, which increases cytokine-independent colony formation; elevated IL-6 and G-CSF mRNA in knockout leukemic cells promotes peripheral neutrophilia; disease acceleration is intrinsic to leukemic cells and not solely niche-dependent. Retroviral BCR-ABL transformation, bone marrow transplantation, methylcellulose colony assay, flow cytometry, Western blot for FAK, qPCR for cytokines Journal of hematology & oncology Medium 24952416
2019 VEGFA-induced co-localization of VEGFR2 with SHB occurs within <2.5 min and is dependent on VEGFR2 tyrosine 1175; SHB then enhances FAK co-localization with VEGFR2; in SHB-deficient endothelial cells FAK/VEGFR2 co-localization is reduced both basally and after VEGFA stimulation, and focal adhesion distribution is altered to a perinuclear location. TIRF (total internal reflection fluorescence) live-cell microscopy of co-localization dynamics, Y1175F-VEGFR2 mutant, SHB-deficient primary lung endothelial cells Cells High 31847469
2020 SHB is an essential scaffold for EphB2-mediated cell segregation; SHB interacts with Nck (via pY297), p120 RasGAP, and α/β-Chimaerin Rac GAPs (via pY246 and pY336 respectively) downstream of EphB2 (and EphA4, EphA8, EphB4); phosphorylation of SHB at Y297, Y246, and Y336 is required for EphB2-ephrinB1 boundary formation and cytoskeletal rearrangement. HEK293 EphB2+/ephrinB1+ cell segregation assay, co-immunoprecipitation, phosphospecific mutagenesis of SHB tyrosines, mass spectrometry interactome The Journal of biological chemistry High 32060095
2020 Conditional SHB inactivation in endothelial cells (Cdh5-CreERt2) reduces tumor growth, reduces vascular leakage, increases hypoxia, and alters adherens junction and focal adhesion gene expression in tumor endothelial cells; conditional SHB inactivation in pericytes (Pdgfrb-CreERt2) decreases pericyte coverage, increases vascular leakage, causes aberrant PDGFRB signaling, and increases lung metastasis without affecting tumor growth, establishing distinct roles of endothelial vs. pericyte SHB. Conditional cell-type-specific Cre-loxP knockout, tumor implantation, flow cytometry, immunofluorescence for vascular markers, RNAseq, vascular permeability assay International journal of cancer High 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
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
2019 Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB. Cells 14 31847469
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
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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