Affinage

CRK

Adapter molecule crk · UniProt P46108

Length
304 aa
Mass
33.8 kDa
Annotated
2026-04-28
100 papers in source corpus 49 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRK is a modular SH2-SH3 adaptor protein that functions as a phosphotyrosine-dependent molecular switch coupling receptor tyrosine kinase, integrin, and cytokine signals to Rac1/Rap1 GTPase activation, actin cytoskeletal reorganization, cell migration, and apoptosis. Its SH2 domain binds tyrosine-phosphorylated substrates (p130CAS, paxillin, Cbl, Dok-7, Dab1) while its N-terminal SH3 domain recruits downstream effectors including C3G, DOCK180, and Abl, thereby activating Rac1 for membrane ruffling and migration, Rap1 for integrin-mediated adhesion and junction formation, and PI3K/Akt for survival and transformation (PMID:9472046, PMID:9808620, PMID:10852971, PMID:25621495). CRK activity is negatively regulated by c-Abl-mediated phosphorylation of Y221, which induces an intramolecular SH2–pY221 interaction that closes the adaptor into an autoinhibited conformation, and positively regulated by Cyclophilin A, which sterically blocks this phosphorylation to maintain the open, active state (PMID:8194526, PMID:7700361, PMID:26656091). CRK-null mice die in late embryogenesis with cardiovascular and craniofacial defects, and tissue-specific deletions reveal essential roles in neuronal positioning (Reelin–Dab1 pathway), neuromuscular synapse formation (Dok-7/MuSK pathway), T cell migration, and ER-stress-induced apoptosis via generation of a BH3-containing cleavage fragment (PMID:16880535, PMID:19074029, PMID:21041412, PMID:22179045).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1990 High

    Establishing that v-Crk uses its SH2 domain to bind phosphotyrosine-containing proteins answered how this adaptor selects its partners and founded the paradigm of SH2-phosphotyrosine recognition in signaling.

    Evidence In vitro binding assays with dephosphorylation controls using bacterially expressed v-Crk

    PMID:1694307 PMID:1705010

    Open questions at the time
    • Identity of endogenous binding partners unknown
    • Cellular context of binding not addressed
  2. 1992 High

    Discovery that CRK is expressed as two splice isoforms (CrkI and CrkII) with dramatically different transforming activities revealed that domain composition—specifically the presence of the C-terminal SH3 domain—acts as an intrinsic negative regulatory element.

    Evidence cDNA cloning, stable expression in rat 3Y1 cells with soft agar and nude mouse assays

    PMID:1630456 PMID:8183562

    Open questions at the time
    • Mechanism by which C-terminal SH3 suppresses transformation not yet defined
    • Relative expression levels of isoforms in normal tissues unknown
  3. 1994 High

    Identification of c-Abl as the kinase that phosphorylates CrkII on Y221, and demonstration that this creates an intramolecular SH2–pY221 interaction that occludes partner binding, established the core autoinhibitory switch mechanism controlling CRK activity.

    Evidence Kinase identification by SH3 binding, in vitro phosphorylation, Y221 mutagenesis, co-immunoprecipitation

    PMID:7926767 PMID:8194526

    Open questions at the time
    • Structural basis of the closed conformation not yet resolved at atomic detail
    • Phosphatase that reverses Y221 phosphorylation unidentified
  4. 1994 High

    Identification of C3G and DOCK180 as SH3-binding effectors, and paxillin as an SH2-binding substrate with defined pYXXP motifs, established CRK as a bridge linking tyrosine-phosphorylated focal adhesion proteins to guanine nucleotide exchange factors for Ras-family GTPases.

    Evidence Expression library screening, GST pulldowns, phosphopeptide motif mapping, surface plasmon resonance

    PMID:7512734 PMID:7537852 PMID:7687742 PMID:8662907

    Open questions at the time
    • Which GTPase (Ras, Rap1, or R-Ras) is the principal downstream target of CRK-C3G in vivo unclear
    • Stoichiometry of complexes not determined
  5. 1995 High

    Direct biophysical demonstration by NMR that phosphorylated CrkII forms a monomeric, intramolecularly closed conformation confirmed the autoinhibition model and ruled out dimerization as a regulatory mechanism.

    Evidence NMR spectroscopy and analytical ultracentrifugation of phosphorylated murine CrkII

    PMID:7700361

    Open questions at the time
    • Full-length multi-domain structure not resolved
    • Dynamics of open-closed transition unknown
  6. 1998 High

    Assembly of the p130CAS–CRK–DOCK180 complex was shown to activate Rac1 and drive cell migration in a Rac-dependent manner, establishing CRK as a central scaffold in integrin-initiated motility signaling.

    Evidence Co-immunoprecipitation, Rac1-GTP pulldowns, dominant-negative epistasis, in vitro migration and in vivo invasion assays

    PMID:9472046 PMID:9808620 PMID:9860979

    Open questions at the time
    • Spatial and temporal regulation of CAS–CRK complex assembly at the leading edge not resolved
    • Relative contributions of Rac1 vs. Rap1 to migration unclear
  7. 2000 High

    v-Crk was shown to constitutively activate the PI3K/AKT pathway as the essential effector for transformation, and NGF-induced Y222 phosphorylation was demonstrated to dynamically dissociate CRK from paxillin controlling adhesion and neuritogenesis, defining CRK as a regulated switch in both oncogenic and differentiation contexts.

    Evidence PI3K inhibitor and constitutively active PI3K rescue in CEFs; kinetic phosphorylation/dissociation analysis with Y222F mutant in PC12 cells

    PMID:10825157 PMID:10852971

    Open questions at the time
    • Direct mechanism linking CRK to PI3K activation not defined
    • Whether CRK directly binds PI3K subunits unclear
  8. 2002 High

    NMR structure of the Abl-SH3/CrkII-SH2-pY221 ternary complex revealed the allosteric coupling whereby phosphopeptide occupancy of the SH2 domain exposes a DE-loop proline-rich site for Abl SH3 docking, explaining how autoinhibition promotes sustained Abl–CRK association.

    Evidence NMR solution structure and 15N relaxation experiments

    PMID:12384576 PMID:8702917

    Open questions at the time
    • No crystal structure of full-length CrkII in the autoinhibited state
    • Kinetic rates of the open-closed transition not measured
  9. 2006 High

    Crk-null mice demonstrated essential in vivo roles in cardiovascular integrity and craniofacial development, converting CRK from a cell-culture signaling node to a gene essential for organogenesis.

    Evidence Cre-loxP conditional knockout with embryonic phenotype analysis

    PMID:16880535

    Open questions at the time
    • Specific cell types and signaling pathways responsible for each defect not dissected
    • Degree of compensation by CrkL not quantified
  10. 2008 High

    Conditional neuronal knockout showed CRK/CrkL are essential downstream mediators of Reelin–Dab1 signaling for cortical neuronal positioning, and that CRK phosphorylation mediates inhibitory NK receptor signaling by terminating activating CRK complexes.

    Evidence Cre-loxP neuronal knockout reproducing reeler phenotype; primary NK cell co-IP and functional rescue with Crk Y-mutant

    PMID:18835194 PMID:19074029

    Open questions at the time
    • Whether CRK activates Rap1 or Rac1 downstream of Dab1 in neurons not resolved
    • Identity of the kinase phosphorylating CRK downstream of inhibitory NK receptors not established
  11. 2010 High

    Discovery that Dok-7 recruits CRK/CrkL upon agrin stimulation and that their muscle-specific deletion causes severe NMJ defects established CRK as critical for neuromuscular synapse formation downstream of MuSK.

    Evidence Dok-7 phosphosite mapping, co-IP with CRK, conditional muscle-specific double KO, NMJ immunohistochemistry

    PMID:21041412

    Open questions at the time
    • Downstream effector (C3G/DOCK180/Rac/Rap) mediating NMJ formation not identified
    • Whether CRK acts pre- or postsynaptically not resolved
  12. 2011 High

    Identification of CRK cleavage during ER stress to generate a BH3-containing fragment that promotes cytochrome c release revealed a non-adaptor, pro-apoptotic function for CRK, establishing it as a direct participant in the mitochondrial apoptosis pathway.

    Evidence Biochemical purification from ER-stressed cells, Crk-null cell apoptosis resistance, isolated mitochondria cytochrome c release assay, BH3 mutagenesis

    PMID:22179045

    Open questions at the time
    • Protease responsible for CRK cleavage not identified
    • Whether BH3 fragment interacts with specific Bcl-2 family members unknown
  13. 2015 High

    Cyclophilin A was identified as a positive regulator that sterically blocks Abl-mediated Y221 phosphorylation, maintaining CRK in the open/active conformation, revealing a novel layer of CRK regulation beyond the Abl–Y221 switch.

    Evidence NMR structure of CypA–CrkII complex, phosphorylation suppression assay, cell migration assay

    PMID:26656091

    Open questions at the time
    • Whether CypA regulation of CRK is stimulus-dependent not addressed
    • Other prolyl isomerases that may regulate CRK not tested
  14. 2018 High

    T cell-specific and lens-specific conditional knockouts demonstrated that CRK integrates chemokine receptor and FGF receptor signals through C3G/Rap1 and Ras/Rac, respectively, controlling integrin-dependent T cell migration and lens fiber elongation.

    Evidence Conditional KO T cells with adhesion/chemotaxis/Rap1 assays; lens double-KO with epistasis and co-IP of Frs2/Shp2/Grb2

    PMID:25621495 PMID:29360039 PMID:30538176

    Open questions at the time
    • Whether CRK-dependent mechanosensing through CasL operates in non-immune cells unknown
    • Redundancy between CRK and CrkL in each tissue context not fully quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the protease cleaving CRK during ER stress, full-length structures of CrkII in open versus closed states at high resolution, and how CRK switches between Rac1 and Rap1 effector output in different physiological contexts.
  • No high-resolution full-length CrkII structure in either state
  • Protease generating BH3 fragment unidentified
  • Context-dependent Rac1 vs. Rap1 selectivity mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 3 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ABL1BCAR1CBLDAB1DOCK1DOK7PXNRAPGEF1
Complex memberships
CRK-C3GPaxillin-GIT2-βPIX-CRKp130CAS-CRK-DOCK180

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 The v-Crk oncoprotein (P47gag-crk) contains SH2 and SH3 domains and binds to phosphotyrosine-containing proteins in a phosphotyrosine-dependent manner; dephosphorylation of binding partners abolishes the interaction, establishing that the SH2 domain mediates phosphotyrosine-dependent protein-protein interactions. In vitro binding assay with dephosphorylation control; domain identification Science High 1694307
1991 The SH2 (and SH2') domains of v-Crk are necessary and sufficient for binding to phosphotyrosine-containing proteins; deletion of SH2 abolishes binding activity. Mutational analysis of bacterially expressed v-Crk domains; in vitro binding assay Molecular and cellular biology High 1705010
1992 Human CRK is expressed as two splice isoforms: CRK-I (SH2 + one SH3) with strong transforming activity and CRK-II (SH2 + two SH3) with low transforming activity, demonstrating that domain composition determines biological activity. cDNA cloning, alternative splicing identification, stable expression in rat 3Y1 cells, soft agar and nude mouse tumor assays Molecular and cellular biology High 1630456
1993 v-Crk binds tyrosine-phosphorylated paxillin via its SH2 domain with subnanomolar affinity; the SH2 binding motif on paxillin is pYDXP; v-Crk binding to paxillin disrupts the kinase-phosphatase balance to increase steady-state paxillin phosphorylation. Co-immunoprecipitation, GST-CrkSH2 pulldown, phosphopeptide library mapping, competitive coprecipitation Molecular and cellular biology High 7687742
1993 Both SH2 and SH3 domains of CRK are required for neuronal differentiation signaling in PC12 cells; CRK SH3 binds proteins of 118, 125, and 136 kDa; CRK-induced neurite formation depends on p21ras activation. Microinjection of wild-type and mutant CRK proteins, peptide competition, antibody neutralization, PC12 neurite assay Molecular and cellular biology High 8321240
1994 c-Abl kinase binds to the first CRK SH3 domain and phosphorylates c-Crk on tyrosine 221 (Y221); this phosphorylation creates a binding site for the Crk SH2 domain, promoting an intramolecular interaction that reduces Crk's ability to bind partner proteins, thereby regulating Crk protein-binding activity. Kinase identification by SH3-domain binding, in vitro phosphorylation, mutagenesis (Y221), co-immunoprecipitation The EMBO journal High 8194526
1994 Abl kinase selects CrkI as a substrate via SH3-binding sites located just C-terminal to the Abl kinase domain; direct interaction between Crk SH3 and Abl occurs in vitro and in mammalian cells, and Crk is phosphorylated on tyrosine when bound to Abl. Yeast two-hybrid, in vitro binding, co-immunoprecipitation from mammalian cells Genes & development High 7926767
1994 C3G, a guanine nucleotide-releasing protein, binds to the CRK SH3 domain via a proline-rich sequence; the CRK-C3G complex may transduce signals from tyrosine kinases to Ras family GTPases. Expression library screening, in vitro binding of bacterially expressed proteins, mutational analysis of SH3 binding region Proceedings of the National Academy of Sciences of the United States of America High 7512734
1994 CRK overexpression enhances NGF-induced Ras activation in PC12 cells via its SH2 and SH3 domains; CRK co-immunoprecipitates with both mSos and C3G (GNRPs for Ras family); CRK SH2 binds tyrosine-phosphorylated Shc after NGF stimulation. Overexpression of wild-type and SH2/SH3 mutant CRK, Ras-GTP pull-down, co-immunoprecipitation Molecular and cellular biology High 8035825
1994 The C-terminal SH3 domain of c-Crk negatively regulates tyrosine phosphorylation of the associated p130 protein; deletion of the C-terminal SH3 (as in v-Crk) results in hyperphosphorylation of p130 and morphological transformation. Construction of SH3 domain deletion mutants, stable expression in rat 3Y1 cells, immunoprecipitation and phosphotyrosine analysis Oncogene High 8183562
1995 pp125FAK phosphorylates paxillin on tyrosine residues 31 and 118, each conforming to the Crk SH2 domain binding motif (P)YXXP, creating high-affinity binding sites for the Crk SH2 domain; FAK must be autophosphorylated and localized to focal adhesions to drive paxillin phosphorylation. FAK-dependent phosphorylation assays, site-directed mutagenesis (Y31, Y118), SH2 domain binding studies Molecular and cellular biology High 7537852
1995 NMR spectroscopy and hydrodynamic measurements directly demonstrated that the SH2 domain of phosphorylated murine CrkII forms an intramolecular interaction with pTyr221; the phosphorylated protein is monomeric, confirming the autoinhibitory intramolecular SH2-pTyr interaction. NMR spectroscopy, hydrodynamic measurements (analytical ultracentrifugation) Nature High 7700361
1996 The SH2 domain of CrkII contains a proline-rich DE loop insert that constitutes a binding site for the Abl SH3 domain; this interaction is potentiated when pTyr221 occupies the CrkII SH2 domain (either intramolecularly or via added phosphopeptide), revealing an allosteric coupling between SH2 phosphopeptide binding and SH3-domain docking. Yeast two-hybrid, in vitro GST pulldown, NMR chemical shift analysis, mutagenesis The Journal of biological chemistry High 8702917
1996 CRK SH3 domain binds DOCK180, C3G, EPS15, and clone ST12; the consensus CRK SH3 binding motif is P+3-P+2-X+1-L0-P-1-X-K; DOCK180 binding affinity to CRK SH3 was measured (Kd ~10^-7 M) by surface plasmon resonance. Far-Western library screening, surface plasmon resonance, mutational analysis The Journal of biological chemistry High 8662907
1996 Upon TCR activation, tyrosine-phosphorylated Cbl binds to the CRK SH2 domain; this association is distinct from constitutive Crk-p130CAS binding and represents a stimulus-dependent switch in Crk binding partners. Co-immunoprecipitation, GST-CrkSH2 pulldown, phosphopeptide binding The Journal of biological chemistry Medium 8626404 8683103
1997 Crk enhances C3G-mediated guanine nucleotide exchange for Rap1 by recruiting C3G to the cell membrane, requiring both SH2 and SH3 domains; membrane-targeted Crk (with farnesylation signal) can substitute for the SH2 domain requirement, showing that membrane recruitment of C3G is the mechanistic basis. Co-expression in COS1 cells, Rap1-GTP pull-down, SH2/SH3 mutants, membrane-targeted constructs The Journal of biological chemistry High 9268367
1997 v-Crk localizes to focal adhesions via its SH2 domain and induces translocation and hyperphosphorylation of p130CAS to the cytoskeleton; both SH2 and SH3 domains are required for increased tyrosine phosphorylation of focal adhesion proteins. Subcellular fractionation, immunolocalization, co-immunoprecipitation, mutational analysis Journal of cell science High 9057091
1998 Anchorage-dependent tyrosine phosphorylation of p130CAS leads to its SH2-mediated coupling with CrkII; this CAS/Crk complex localizes to membrane ruffles and functions as a 'molecular switch' for cell migration in a Rac-dependent (but Ras-independent) manner. Co-immunoprecipitation, expression of CAS/Crk mutants, dominant-negative GTPases, in vitro migration assay, in vivo invasion assay The Journal of cell biology High 9472046
1998 DOCK180 binds directly to the CRK SH3 domain and activates Rac1 (increases GTP-bound Rac1); co-expression of CrkII and p130CAS enhances DOCK180-dependent Rac1 activation; dominant-negative Rac1 suppresses DOCK180-induced membrane spreading. Co-immunoprecipitation, Rac1-GTP pull-down (GST-PAK), dominant-negative Rac1, JNK activation assay Genes & development High 9808620
1998 Crk connects multiple extracellular stimuli (EGF, integrins, v-Src) to the Rac-JNK pathway; CAS/Crk complex is specifically required for integrin-mediated (but not EGF- or v-Src-mediated) JNK activation; dominant-negative Crk SH2 or SH3 mutants block JNK activation. Transient expression of Crk and domain mutants, dominant-negative GTPases and Crk mutants, JNK kinase assay Proceedings of the National Academy of Sciences of the United States of America High 9860979
2000 v-Crk constitutively activates the PI3K/AKT pathway (but not MAPK or JNK pathways) in transformed CEF; both SH2 and SH3 domains are required; PI3K inhibitor LY294002 suppresses v-Crk transformation, placing PI3K/AKT as the essential effector pathway for v-Crk-induced transformation. SH2/SH3 domain mutant analysis, pathway-specific kinase assays, PI3K inhibitor, constitutively active PI3K expression Proceedings of the National Academy of Sciences of the United States of America High 10852971
2000 Phosphorylation of paxillin tyrosines 31 and 118 is required for CrkII SH2 domain binding and for collagen-induced cell migration; mutation of both tyrosines prevents paxillin-Crk complex formation and abrogates motility without affecting adhesion or spreading. Paxillin Y31F/Y118F mutants, co-immunoprecipitation, cell migration assay, dominant-negative CrkII SH2/SH3 mutants The Journal of cell biology High 10704446
2000 c-Abl phosphorylates c-CrkII on the negative regulatory Tyr222 (corresponding to Y221 in mouse) in response to NGF; this phosphorylation causes dissociation of Crk from paxillin and from c-Abl, and cells expressing a Y222F Crk mutant show defective adhesion and neuritogenesis, demonstrating the functional importance of the Abl-Crk phosphorylation cycle. Transient co-transfection, kinetics of phosphorylation and complex dissociation in PC12 cells, co-immunoprecipitation, Y222F point mutant The Journal of biological chemistry High 10825157
2000 v-Crk activates JNK via C3G and R-Ras (not Rap1); constitutively active R-Ras activates JNK, and dominant-negative R-Ras suppresses v-Crk-induced JNK activation and flat reversion of v-Crk-transformed cells. Dominant-negative R-Ras, constitutively active GTPase constructs, JNK assay, flat-reversion assay in NIH 3T3 cells The Journal of biological chemistry Medium 10777559
2001 Crk family adaptor proteins trans-activate c-Abl kinase through the interaction of the Crk N-terminal SH3 domain with Abl proline-rich motifs; Abl activation by Crk is negatively regulated by phosphorylation of CrkY221 (which engages the CrkII SH2 domain intramolecularly, freeing the C-terminal SH3 to bind Abl). Co-immunoprecipitation, in vitro kinase assay, SH2/SH3 mutants, Y221 phosphorylation-deficient mutants Genes to cells Medium 11380621
2002 NMR solution structure of the ternary complex of Abl SH3 domain, Crk SH2 domain (bound to Crk pY221 phosphopeptide) revealed that pY221-occupied Crk SH2 domain presents a DE-loop proline-rich site for Abl SH3 binding; the two domains are tethered but flexibly oriented, illustrating highly modular SH2-SH3 regulatory interactions. NMR solution structure determination, 15N relaxation experiments Proceedings of the National Academy of Sciences of the United States of America High 12384576
2002 CAS/Crk scaffold assembly in pseudopodia is required for translocation and activation of Rac1 at the leading edge; Rac1 activation creates a positive-feedback loop to maintain CAS/Crk coupling; disassembly of CAS/Crk is required for pseudopodia retraction and is independent of FAK activity. Biochemical pseudopodia purification, Rac1-GTP pull-down, dominant-negative Rac1, CAS/Crk mutants The Journal of cell biology High 11839772
2002 Crk adaptor protein is required for ephrin-B1-induced membrane ruffling and focal complex assembly in endothelial cells; Crk is recruited to nascent focal complexes via p130CAS (not paxillin); Crk signals through Rac1 for membrane ruffling and through Rap1 for focal complex stabilization. Live fluorescence imaging (DsRed-Crk), RNAi knockdown, dominant-negative Crk mutants, dominant-negative Rac1/Rap1GAPII Molecular biology of the cell High 12475948
2002 The C-terminal SH3 domain of Crk contains a binding site for the nuclear export factor Crm1; a nuclear export-deficient Crk mutant promotes apoptosis and interacts strongly with the nuclear tyrosine kinase Wee1 via its SH2 domain, suggesting a nuclear CRK-Wee1 complex promotes apoptosis. Co-immunoprecipitation of Crk with Crm1 and Wee1, NES mutant Crk expression, apoptosis assay Molecular and cellular biology Medium 11839808
2003 Pseudomonas aeruginosa ExoT ADP-ribosylates CrkI and CrkII (but not by ExoS); ADP-ribosylation of Crk is responsible for the anti-phagocytosis phenotype of ExoT in mammalian cells. 2D-SDS-PAGE, MALDI-TOF mass spectrometry identification, in vitro ADP-ribosylation assay with recombinant Crk The Journal of biological chemistry High 12807879
2003 CrkII associates with a multimolecular Paxillin/GIT2/β-PIX complex in a Rac-dependent manner; this complex promotes paxillin relocalization to focal contacts and lamellipodia formation; both SH2 and N-terminal SH3 domains of CrkII are required. Co-immunoprecipitation, stable cell lines, dominant-negative Rac1, SH2/SH3 domain mutants, paxillin localization by immunofluorescence Molecular biology of the cell High 12857867
2004 Crk directly interacts with tyrosine-phosphorylated cortactin and conditions cortactin-dependent actin polymerization required for Shigella uptake; Crk SH2 domain mutant and Arp2/3-binding-deficient cortactin both block bacterial actin foci formation. Co-immunoprecipitation of Crk with phospho-cortactin, RNAi knockdown, overexpression of WT and domain mutants, actin foci assay The Journal of cell biology High 15263018
2004 Nectin-induced Cdc42 activation and adherens junction formation proceed through a c-Src–Crk–C3G–Rap1 signaling cascade; Rap1 is recruited and locally activated at nectin-based contact sites; activation of both c-Src and Rap1 is essential for FRG (a Cdc42 GEF) activation. Co-immunoprecipitation, dominant-negative Crk/C3G/Rap1, Rac/Cdc42 activation assays, adherens junction formation assay The Journal of biological chemistry High 15504743
2006 Crk-null mice die in late embryogenesis with cardiovascular defects (edema, hemorrhage, cardiac defects) and craniofacial abnormalities (cleft palate), demonstrating essential in vivo roles for Crk in vascular smooth muscle integrity and cardiac/craniofacial development. Cre-loxP conditional knockout, immunohistochemistry, embryonic phenotype analysis Molecular and cellular biology High 16880535
2007 NMR solution structures of CrkI, CrkII, and phosphorylated CrkII revealed that the linker region between SH3 domains modulates target binding and determines differential transforming activity; intramolecular SH2-pY221 interaction in phospho-CrkII occludes the SH2 binding surface; CrkI (lacking C-terminal SH3 and linker) adopts a constitutively open, active conformation. NMR structure determination, mutational analysis in 3Y1 fibroblasts, transformation assay Nature structural & molecular biology High 17515907
2007 Influenza NS1 proteins of the 1918 pandemic and avian strains bind the N-terminal SH3 domain of CRK and CrkL via a consensus PxxP motif; this interaction is associated with enhanced PI3K/Akt signaling in host cells. SH3 phage-display library screening, recombinant protein binding, co-precipitation from infected cells, Akt phosphorylation assay The Journal of biological chemistry Medium 18165234
2008 Inhibitory NK cell receptor signaling induces tyrosine phosphorylation of Crk (concomitant with Vav1 dephosphorylation); phospho-Crk dissociates from C3G and binds c-Abl; membrane-targeted Tyr-mutant Crk overrides inhibitory receptor signaling, demonstrating that Crk phosphorylation is a functional component of the inhibitory mechanism. Co-immunoprecipitation of Crk complexes before/after inhibitory receptor engagement, membrane-targeted Crk mutant overexpression, NK cytotoxicity assay Immunity High 18835194
2008 Crk and CrkL are essential downstream mediators of the Reelin pathway acting through Dab1; their conditional knockout in neurons reproduces reeler phenotype; Reelin-induced phosphorylation of C3G and Akt (but not Dab1 turnover) is absent in neurons lacking Crk/CrkL, placing C3G and Akt phosphorylation downstream of Crk/CrkL. Cre-loxP conditional knockout, immunohistochemistry, primary cortical neuron signaling assays The Journal of neuroscience High 19074029
2008 Abl PxxP motifs inhibit Crk signaling during cell spreading; Crk SH3 binding to Abl PxxP motifs is required for coordinated regulation of filopodia and focal adhesion formation; silencing or overexpression of Crk combined with pharmacological Abl inhibition and PxxP mutants defines distinct Crk- and Nck-dependent mechanisms. SH3 phage-display library, protein overexpression, gene silencing (RNAi), pharmacological inhibitors, mutational analysis, cell-spreading assay Journal of cell science Medium 18768933
2009 CrkII preferentially activates Rac1 (requiring C-terminal SH3 domain), while CrkI and variants lacking a functional C-terminal SH3 domain preferentially activate Rap1; Crk-dependent signaling is required for PDGF-stimulated focal adhesion formation and actin remodeling; Abl family kinases terminate Crk signaling by phosphorylating Y221. Gene silencing, isoform-specific rescue with mutants, Rac1/Rap1 activity assays, focal adhesion analysis, PDGF stimulation Journal of cell science High 19861495
2010 Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, recruiting Crk and CrkL; selective inactivation of Crk/CrkL in skeletal muscle causes severe neuromuscular synapse defects in vivo, revealing a critical role for Crk downstream of Dok-7/MuSK in pre- and postsynaptic differentiation. Phosphorylation site mapping of Dok-7, co-immunoprecipitation of Crk/CrkL with Dok-7, conditional muscle-specific knockout, immunohistochemistry of NMJ morphology Genes & development High 21041412
2011 CRK is cleaved during ER stress to generate an N-terminal ~14 kDa fragment; this fragment contains a BH3 domain that sensitizes isolated mitochondria to cytochrome c release; Crk-null cells are strongly resistant to ER-stress-induced apoptosis; mutation of the BH3 domain reduces apoptotic activity. Biochemical purification of pro-apoptotic activity from ER-stressed cells, Crk-null cell lines, isolated mitochondria cytochrome c release assay, BH3 domain mutagenesis Nature cell biology High 22179045
2012 At NK cell activating synapses, Crk is required for movement of Fc microclusters and buildup of F-actin; at inhibitory synapses, Crk phosphorylation blocks both Crk-dependent activation signals and F-actin network formation, providing a unified mechanism for inhibitory receptor function. Primary NK cell imaging over lipid bilayers, Crk-deficient NK cell analysis, F-actin measurement, microcluster tracking Immunity High 22464172
2013 Loss of both Crk and CrkL in fibroblasts causes rounded morphology, loss of focal adhesions, reduced actin stress fibers, collapse of microtubule structures, decreased spontaneous motility, and reduced p130CAS phosphorylation; CrkII rescues the phenotype more effectively than CrkL, demonstrating overlapping but distinct functions. Conditional double-knockout fibroblasts (Cre-loxP), actin/tubulin staining, focal adhesion analysis, wound-healing assay, isoform rescue experiments Oncogene High 24166500
2015 Cyclophilin A (CypA) binds CrkII at the pTyr221 site, sterically restricting kinase access and thereby suppressing CrkII phosphorylation; this maintains CrkII in the active (open) conformation and promotes Abl-Crk signaling and cell migration. NMR structure of CypA-CrkII interaction, biophysical binding assays, phosphorylation suppression assay, cell migration assay in CypA/CrkII overexpressing cancer cells Nature chemical biology High 26656091
2015 T cells lacking Crk and CrkL exhibit reduced integrin-dependent adhesion, chemotaxis, and diapedesis; Crk coordinates with C3G and CasL to activate RAP1 downstream of chemokine receptors; CRK proteins selectively regulate effector T cell migration into inflamed sites but not to lymphoid organs. Conditional T cell-specific knockout, integrin adhesion assay, chemotaxis assay, diapedesis assay, Rap1 activation assay, GVHD/GVL mouse model The Journal of clinical investigation High 25621495
2018 Crk proteins are required for FGF-induced lens fiber cell elongation downstream of FGF receptor; Crk interacts with Frs2, Shp2, and Grb2 upon FGF stimulation; genetic ablation and epistasis show Crk acts downstream of FGF signaling, with partial compensation by Ras and Rac activation. Conditional knockout (Crk/Crkl double KO in lens), genetic epistasis, co-immunoprecipitation of Crk with Frs2/Shp2/Grb2, cell morphology analysis eLife High 29360039
2018 Crk proteins are required for LFA-1–induced actin polymerization, leading edge formation, and T cell migration; Crk mediates LFA-1 signaling-induced phosphorylation of c-Cbl and its association with p85 (PI3K subunit), promoting PI3K activity and cytoskeletal remodeling; Crk is also required for T cell mechanosensing via differential phosphorylation of force-sensitive CasL. Crk conditional KO T cells, actin polymerization assay, co-immunoprecipitation of Cbl-p85, PI3K activity assay, substrate stiffness assay, CasL phosphorylation analysis Science signaling High 30538176

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 CAS/Crk coupling serves as a "molecular switch" for induction of cell migration. The Journal of cell biology 590 9472046
1995 pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Molecular and cellular biology 523 7537852
2001 Crk family adaptors-signalling complex formation and biological roles. Oncogene 407 11607838
1990 Binding of transforming protein, P47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science (New York, N.Y.) 392 1694307
1998 Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes & development 377 9808620
1994 C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proceedings of the National Academy of Sciences of the United States of America 371 7512734
1994 c-Abl kinase regulates the protein binding activity of c-Crk. The EMBO journal 348 8194526
1994 Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes & development 316 7926767
1993 Identification and characterization of a high-affinity interaction between v-Crk and tyrosine-phosphorylated paxillin in CT10-transformed fibroblasts. Molecular and cellular biology 265 7687742
1992 Two species of human CRK cDNA encode proteins with distinct biological activities. Molecular and cellular biology 262 1630456
2000 Phosphorylation of tyrosine residues 31 and 118 on paxillin regulates cell migration through an association with CRK in NBT-II cells. The Journal of cell biology 253 10704446
2009 Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell communication and signaling : CCS 224 19426560
1993 Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 214 8361759
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2003 Pseudomonas aeruginosa ExoT ADP-ribosylates CT10 regulator of kinase (Crk) proteins. The Journal of biological chemistry 129 12807879
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2007 Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. The Journal of biological chemistry 87 18165234
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