Affinage

CRK

Adapter molecule crk · UniProt P46108

Length
304 aa
Mass
33.8 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRK is an SH2/SH3-domain adaptor protein that converts tyrosine-phosphorylation events into the activation of small GTPase and kinase cascades governing cell adhesion, migration, survival, and apoptosis (PMID:1694307, PMID:1690891, PMID:9472046). Its SH2 domain engages tyrosine-phosphorylated partners through a pYDXP consensus—including paxillin, p130CAS, Wee1, Dab1, and receptor sites such as VEGFR-3 Y1063 (PMID:7687742, PMID:11134069, PMID:16076871, PMID:19074029)—while its N-terminal SH3 domain recruits proline-rich effectors including the GEFs C3G and mSos, DOCK180, and c-Abl, thereby coupling upstream receptors to Rac1, Rap1, and Ras-family GTPase activation and downstream JNK, ERK, and PI3K/AKT signaling (PMID:8035825, PMID:8657152, PMID:9268367, PMID:10852971). CAS/Crk complex formation acts as a phosphorylation-gated molecular switch for Rac-dependent membrane ruffling, migration, and invasion, and the two splice isoforms differ functionally—CRK-I is transforming and biases toward Rap1, whereas CRK-II carries a second SH3 domain and biases toward Rac1 (PMID:1630456, PMID:9472046, PMID:19861495). CRK signaling is held in check by c-Abl-mediated phosphorylation of Tyr221, which folds the protein into an intramolecular SH2–pY221 inhibitory state; cyclophilin A binds this site to block phosphorylation and lock CRK in the open, migration-promoting conformation, and PAK1-mediated Ser41 phosphorylation further promotes motility (PMID:8194526, PMID:7926767, PMID:8702917, PMID:26656091, PMID:22848689). Beyond its adaptor role, CRK is a required pro-apoptotic effector: it transduces apoptotic signaling in Xenopus extracts via a Wee1–SH2 interaction, and during ER stress it is cleaved to an N-terminal BH3-containing fragment that sensitizes mitochondria to cytochrome c release (PMID:9029144, PMID:11134069, PMID:22179045). In vivo, conditional inactivation of Crk/CrkL establishes essential roles in Reelin-directed neuronal positioning and dendritogenesis, FGF-driven lens fiber elongation, neuromuscular synapse formation, and integrin/LFA-1-dependent T-cell adhesion and trafficking (PMID:19074029, PMID:21041412, PMID:25621495, PMID:30538176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1990 High

    Established the founding principle that CRK's SH2/SH3 domains mediate phosphotyrosine-dependent protein interactions, defining it as an adaptor rather than an enzyme.

    Evidence In vitro binding of bacterially expressed v-Crk to phosphotyrosine proteins with a dephosphorylation control

    PMID:1690891 PMID:1694307

    Open questions at the time
    • Did not identify specific cellular binding partners
    • No consensus binding motif defined
  2. 1991 High

    Localized phosphotyrosine-binding activity specifically to the SH2 domain, separating the two modular functions.

    Evidence Deletion/point mutagenesis of v-Crk fragments in binding assays

    PMID:1705010

    Open questions at the time
    • Did not define the SH3 ligand repertoire
    • No physiological substrate identified
  3. 1992 High

    Showed the two CRK splice isoforms are functionally distinct, with CRK-I transforming cells while CRK-II does not, framing isoform identity as a determinant of biological output.

    Evidence Stable expression in rat 3Y1 cells, soft-agar and nude-mouse xenograft assays

    PMID:1630456

    Open questions at the time
    • Molecular basis of the isoform difference not resolved here
    • Downstream effectors unknown
  4. 1993 High

    Defined the pYDXP consensus for the CRK SH2 domain and identified phosphopaxillin as a high-affinity ligand, giving the adaptor a sequence code for partner selection.

    Evidence Co-IP, GST-SH2 pulldown, phosphopeptide library mapping, competition

    PMID:7687742

    Open questions at the time
    • Cellular consequence of paxillin binding not yet established
    • Full ligand repertoire incomplete
  5. 1994 High

    Uncovered the Tyr221 autoinhibitory mechanism—c-Abl binds CRK SH3 and phosphorylates Y221, creating an intramolecular SH2 lock that shuts off complex formation—defining the core negative-regulatory switch.

    Evidence In vitro kinase assay, mutagenesis, comparison of bacterial vs mammalian protein, co-IP

    PMID:7926767 PMID:8194526

    Open questions at the time
    • How the lock is physiologically relieved not addressed
    • Kinetics of switching unknown
  6. 1994 High

    Connected CRK SH3 to Ras-family GTPase activation by identifying mSos and C3G as effectors and showing CRK enhances NGF-induced Ras activation.

    Evidence Co-IP from PC12 cells, Ras activation assay, dominant-negative CRK mutants

    PMID:8035825

    Open questions at the time
    • Did not separate Ras vs Rap1 outputs
    • Membrane recruitment mechanism not yet defined
  7. 1995 High

    Placed CRK in the focal-adhesion axis by showing FAK recruits p130CAS, which upon phosphorylation recruits CRK SH2, linking integrin/FAK signaling to the adaptor.

    Evidence Yeast two-hybrid, co-IP from fibroblasts, deletion mapping

    PMID:7479864

    Open questions at the time
    • Downstream GTPase output of the FAK-CAS-CRK module not defined here
  8. 1996 High

    Identified DOCK180 as a major CRK SH3 effector whose membrane targeting drives cell-shape change, and used NMR to show Y221 phosphorylation triggers a conformational change exposing an SH3-binding loop, refining the autoinhibition model.

    Evidence Far Western/cDNA cloning with farnesylated DOCK180 morphology assay; yeast two-hybrid, GST pulldown, NMR, phosphopeptide competition

    PMID:8657152 PMID:8702917

    Open questions at the time
    • GTPase activated by DOCK180 not yet identified
    • Physiological trigger for the conformational switch unresolved
  9. 1997 High

    Defined the recruitment-based mechanism of GTPase activation: CRK enhances C3G GEF activity toward Rap1 by membrane localization rather than allosteric activation.

    Evidence Co-expression in COS1, Rap1 activation assay, dominant-negative and farnesylated-CRK rescue

    PMID:9268367

    Open questions at the time
    • Whether Rac and Ras are activated by the same recruitment logic not tested here
  10. 1997 High

    Revealed an unexpected pro-apoptotic function: CRK is required for apoptosis in Xenopus egg extracts and its SH2 domain alone can block apoptosis, dissociating its survival/adaptor roles from a distinct death-signaling role.

    Evidence Cell-free Xenopus extract immunodepletion, antibody inhibition, recombinant protein rescue

    PMID:9029144

    Open questions at the time
    • The SH2 partner driving apoptosis not yet identified
    • Relevance to mammalian apoptosis untested
  11. 1998 High

    Established CAS/Crk coupling as a phosphorylation-gated molecular switch for migration via Rac (not Ras), and demonstrated CRK-dependent JNK activation downstream of EGF, integrin, and v-Src, tying the adaptor to stress-kinase signaling.

    Evidence Migration and invasion assays, co-IP, dominant-negative GTPases; JNK kinase assays with CRK mutants

    PMID:9472046 PMID:9566923 PMID:9860979

    Open questions at the time
    • GEF linking CAS/Crk to Rac not pinpointed
    • Reconciliation of Rho vs Rac outputs across contexts incomplete
  12. 2000 High

    Expanded the effector network—v-Crk constitutively activates PI3K/AKT (required for transformation) and routes JNK activation through C3G→R-Ras→MLK3—while CAS/Crk coupling was shown to jointly drive invasion and suppress apoptosis.

    Evidence PI3K inhibitor/dominant-active PI3K transformation assays; JNK reporter with dominant-negative GTPases; 3D collagen invasion/apoptosis assays

    PMID:10747099 PMID:10777559 PMID:10852971

    Open questions at the time
    • How CRK selects among Rac/Rap1/R-Ras outputs context-dependently not resolved
    • Direct PI3K-CRK linkage mechanism left open
  13. 2000 High

    Identified phospho-Wee1 as the specific CRK SH2 partner driving apoptosis, giving the death function a defined molecular input.

    Evidence Xenopus extract immunodepletion, recombinant Wee1 rescue, co-IP

    PMID:11134069

    Open questions at the time
    • Downstream apoptotic effectors of the Wee1-Crk complex not defined
    • Mammalian counterpart untested at this stage
  14. 2002 High

    Showed Y221 phosphorylation, beyond simple autoinhibition, is required to promote Rac membrane translocation, and connected nuclear export (Crm1) regulation to the Wee1-dependent apoptotic function.

    Evidence CrkII-Y221F mutagenesis with membrane fractionation and migration assays; Crm1/Wee1 co-IP with NES-mutant apoptosis assay

    PMID:11839808 PMID:12198159

    Open questions at the time
    • Mechanism coupling Y221 phosphorylation to Rac translocation not fully defined
    • Nuclear localization of CRK not independently verified (#22)
  15. 2002 High

    Demonstrated pathogen subversion of CRK: Pseudomonas ExoT ADP-ribosylates Arg20 in the SH2 domain to block p130CAS/paxillin binding and disable Rac1-dependent functions, validating the SH2 docking step as functionally essential.

    Evidence Mass spectrometry site ID, GST pulldown, far Western, R20K mutagenesis, Rac1 rescue

    PMID:16123042

    Open questions at the time
    • In vivo consequences during infection not addressed
  16. 2006 High

    Extended CRK to receptor-specific survival signaling, defining VEGFR-3 Y1063 as a direct CRK recruitment site feeding MKK4→JNK prosurvival signaling, and the EphB4→Abl→Crk axis as a tumor-suppressive pathway.

    Evidence Systematic VEGFR-3 tyrosine mutants with JNK assay/RNAi; ephrin-B2 stimulation with pathway inhibition and xenografts

    PMID:16076871 PMID:16862147

    Open questions at the time
    • How the same JNK module yields pro-survival vs anti-proliferative outcomes context-dependently unresolved
  17. 2003 Medium

    Placed CRK within a Paxillin/GIT2/β-PIX adhesion complex and, with later work, showed GIT2 represses Crk/Rac1-driven lamellipodial extension, defining a built-in brake on CRK adhesion signaling.

    Evidence Co-IP of multiprotein complex with paxillin mutants and spreading assays; GIT2 siRNA with Crk-dependent migration epistasis

    PMID:12857867 PMID:16628223

    Open questions at the time
    • Single-lab co-IP evidence for complex stoichiometry
    • Direct vs indirect GIT2-Crk relationship not fully resolved
  18. 2008 High

    Established CRK as a regulated node in immune-cell signaling: NK inhibitory receptors phosphorylate CRK to switch it from C3G to c-Abl, and Crk/CrkL act as essential Reelin effectors downstream of Dab1 in neurons.

    Evidence NK cytotoxicity assays with membrane-targeted CRK mutants; conditional Crk/CrkL knockout neurons with C3G/Akt phospho-readouts; RNAi dendritogenesis assays

    PMID:18477607 PMID:18835194 PMID:19074029

    Open questions at the time
    • How the same phosphorylation acts inhibitory in NK cells but is regulatory elsewhere not unified
    • Effectors downstream of the Dab1-Crk node only partially mapped
  19. 2009 High

    Resolved the isoform-specific GTPase bias—CrkII/CrkL (with C-terminal SH3) favor Rac1 while CrkI favors Rap1—and showed Abl-mediated Y221 phosphorylation terminates CRK signaling to drive focal-adhesion turnover.

    Evidence Isoform-specific rescue, GTPase activation assays, PDGF stimulation, focal-adhesion analysis

    PMID:19861495

    Open questions at the time
    • Structural basis for differential GEF selection across isoforms not defined
  20. 2011 High

    Defined a mammalian pro-apoptotic mechanism: ER stress cleaves CRK to an N-terminal BH3-containing fragment that sensitizes mitochondria to cytochrome c release, with Crk-/- cells resistant to ER-stress apoptosis.

    Evidence Biochemical fragment purification, Crk-/- cells, isolated-mitochondria cytochrome c release, BH3 mutagenesis

    PMID:22179045

    Open questions at the time
    • Protease responsible for CRK cleavage not identified
    • Link between the apoptotic fragment and the adaptor's signaling functions unresolved
  21. 2012 Medium

    Connected CRK to actin-based immune-synapse dynamics and added PAK1-mediated Ser41 phosphorylation as a second regulatory input promoting motility.

    Evidence Live imaging of NK cells with conditional knockout and F-actin/microcluster tracking; phosphomimetic/deficient Ser41 mutants with PAK1 RNAi rescue

    PMID:22464172 PMID:22848689

    Open questions at the time
    • Ser41 phosphorylation evidence single-lab
    • Integration of Ser41 with Y221 regulation not addressed
  22. 2015 High

    Provided structural and biophysical evidence that cyclophilin A binds the Y221 site to block kinase access and lock CRK open, and defined an in vivo CRK/C3G/CasL→RAP1 axis governing integrin-dependent T-cell adhesion and trafficking.

    Evidence Structural/biophysical binding with phosphorylation and migration assays; conditional knockout mice with adhesion, chemotaxis, RAP1 and trafficking readouts

    PMID:25621495 PMID:26656091

    Open questions at the time
    • Physiological contexts where CypA gating dominates over Abl phosphorylation not delineated
  23. 2018 High

    Cemented CRK's developmental roles in vivo—FGF-driven lens fiber elongation via Frs2/Shp2/Grb2 coupling, and LFA-1 outside-in signaling for T-cell migration through c-Cbl/PI3K and mechanosensing—rescuable in part by Ras/Rac activation.

    Evidence Conditional knockout mice, epistasis, co-IP, Ras/Rac rescue; LFA-1 stimulation with c-Cbl/p85 co-IP, PI3K assay, stiffness substrates

    PMID:29360039 PMID:30538176

    Open questions at the time
    • Direct vs scaffolded role of CRK in c-Cbl/PI3K assembly not fully resolved
    • Mechanotransduction mechanism beyond CasL phosphorylation incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRK integrates its multiple regulatory inputs (Y221/Abl, Ser41/PAK1, CypA, ExoT, ER-stress cleavage) into context-specific decisions between adhesion/migration, GTPase selection, and apoptosis remains unresolved.
  • No unified quantitative model of CRK conformational state vs output
  • Protease and full cleavage pathway for the BH3 fragment unidentified
  • Determinants selecting Rac vs Rap1 vs R-Ras in a given cell type undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-5357801 Programmed Cell Death 3
Partners
ABL1BCAR1DOCK180PPIAPXNRAPGEF1SOS1WEE1
Complex memberships
Paxillin/GIT2/β-PIX complexp130CAS/Crk complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 P47gag-crk (v-Crk oncogene product) contains SH2 and SH3 domains and binds phosphotyrosine-containing proteins from transformed cells in vitro; the association with p60v-src was abolished by dephosphorylation, establishing that SH2/SH3 domains mediate phosphotyrosine-dependent protein interactions. In vitro binding assay with bacterially expressed crk protein, dephosphorylation experiment Science High 1690891 1694307
1991 The SH2 domain (and SH2') of v-Crk is necessary and sufficient for binding to phosphotyrosine-containing proteins; deletion of the SH2 domain abolishes binding activity. Deletion/point mutant analysis of bacterially expressed v-Crk fragments in binding assays Molecular and cellular biology High 1705010
1992 CRK-I (one SH2, one SH3) and CRK-II (one SH2, two SH3) are alternative splice products with distinct biological activities: CRK-I expression in rat 3Y1 cells causes anchorage-independent growth and tumor formation in nude mice, whereas CRK-II does not. Stable expression in rat 3Y1 cells, soft-agar colony assay, nude mouse xenograft Molecular and cellular biology High 1630456
1993 The CRK SH2 domain binds tyrosine-phosphorylated paxillin with sub-nanomolar affinity; the preferred binding motif is pYDXP. v-Crk co-immunoprecipitates paxillin from CT10-transformed cells. Co-immunoprecipitation, GST-CrkSH2 pulldown, phosphopeptide library mapping, competitive inhibition with phosphopeptide Molecular and cellular biology High 7687742
1994 c-Abl kinase binds to the first CRK SH3 domain via proline-rich motifs and phosphorylates c-Crk on tyrosine 221 (Y221). Phosphorylation of Y221 creates an intramolecular binding site for the Crk SH2 domain, rendering c-Crk unable to form complexes with other proteins. Bacterially expressed (unphosphorylated) c-Crk binds multiple proteins; mammalian (Y221-phosphorylated) c-Crk remains uncomplexed. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, bacterial expression The EMBO journal High 7926767 8194526
1994 Crk-I SH3 domain directly interacts with novel proline-rich sites (~10 aa) just C-terminal to the Abl kinase domain; when bound to Abl, Crk-I is phosphorylated on tyrosine, establishing these SH3-binding sites as substrate recognition sites for Abl kinase. Yeast two-hybrid, in vitro binding, co-immunoprecipitation from mammalian cells Genes & development High 7926767
1994 CRK binds two guanine nucleotide-releasing proteins for Ras family GTPases: mSos and C3G. Both are co-immunoprecipitated with endogenous Crk in PC12 cells. CRK overexpression enhances NGF-induced Ras activation; SH2 or SH3 domain mutants of CRK-I inhibit this activation. Co-immunoprecipitation, Ras activation assay, dominant-negative mutant expression Molecular and cellular biology High 8035825
1995 p130CAS (Crk-associated substrate) interacts with FAK via the p130CAS SH3 domain binding to a proline-rich region in FAK (APPKPSR, residues 711-717). p130CAS and FAK co-immunoprecipitate from mouse fibroblasts, and p130CAS subsequently recruits Crk SH2 upon tyrosine phosphorylation, linking FAK to Crk signaling. Yeast two-hybrid, co-immunoprecipitation from fibroblasts, deletion mapping PNAS High 7479864
1996 DOCK180 (180 kDa) is a major CRK SH3-binding protein. Membrane targeting of DOCK180 (by farnesylation signal) changes cell morphology from spindle to flat/polygonal, demonstrating DOCK180 is a downstream effector of CRK at the cell membrane. Far Western blotting, cDNA cloning, farnesylated DOCK180 overexpression, morphological analysis Molecular and cellular biology High 8657152
1996 A proline-rich insert in the CRK-II SH2 domain (DE loop) functions as an SH3-domain-binding site that interacts with the Abl SH3 domain. Phosphorylation of Tyr-221 induces an intramolecular SH2-pTyr221 interaction that causes a conformational change (detected by NMR) exposing the proline-rich insert and promoting interaction with the Abl SH3 domain. Yeast two-hybrid, GST-pulldown, NMR spectroscopy, phosphopeptide competition The Journal of biological chemistry High 8702917
1997 C3G (Crk SH3-binding GEF) activates Rap1 and is recruited to the cell membrane by Crk, CrkL, and Grb2. This membrane recruitment (not allosteric activation) is the mechanism by which Crk enhances C3G guanine nucleotide exchange activity for Rap1; both SH2 and SH3 domains of Crk are required, and a farnesylated Crk lacking the SH2 domain can substitute. Co-expression in COS1 cells, Rap1 activation assay (GTP/GDP ratio), dominant-negative mutants, farnesylated Crk rescue experiment The Journal of biological chemistry High 9268367
1997 Crk is required for apoptosis in Xenopus egg extracts: immunodepletion of endogenous Crk or addition of anti-Crk antisera prevents apoptosis; addition of recombinant Crk protein restores apoptosis. The SH2 domain of Crk (but not other SH2 domains tested) is sufficient to prevent apoptosis when added exogenously. Cell-free Xenopus egg extract, immunodepletion, antibody inhibition, recombinant protein reconstitution The EMBO journal High 9029144
1998 CAS/Crk complex formation serves as a 'molecular switch' for cell migration: anchorage-dependent tyrosine phosphorylation of p130CAS creates an SH2-binding site for Crk; CAS/Crk coupling localizes to membrane ruffles and induces migration via Rac (not Ras). CAS lacking the Crk-binding site or Crk with mutant SH2 blocks cytokine-stimulated migration. Cell migration assays, co-immunoprecipitation, dominant-negative GTPase expression, in vivo invasion assay The Journal of cell biology High 9472046
1998 Crk mediates JNK activation via a pathway requiring both SH2 and SH3 domains. p130CAS-Crk complex formation leads to Rac-dependent JNK activation. Dominant-negative Crk mutants block EGF, integrin, and v-Src-induced JNK activation. JNK kinase assay, dominant-negative mutant expression, co-immunoprecipitation PNAS High 9860979
1998 v-Crk activates Rho-dependent cell spreading and focal adhesion biogenesis in PC12 cells. v-Crk expression requires both SH2 and SH3 domains; v-Crk co-transfection with p160ROCK causes hyperactivation of p160ROCK. v-Crk does not activate Rac- or Cdc42-dependent kinases PAK or S6K. Dominant-negative C3 toxin, SH2/SH3 mutants, co-transfection assays, immunohistochemistry, PI(4,5)P2 measurement Molecular and cellular biology Medium 9566923
1999 p130CAS and Crk couple Pyk2 to JNK (but not ERK) activation. Dominant-negative p130CAS or Crk specifically inhibits Pyk2-induced JNK but not ERK activity, defining the Pyk2→Src→p130CAS→Crk→JNK pathway. Dominant-negative mutant overexpression, ERK and JNK activation assays The Journal of biological chemistry Medium 10329689
2000 CAS/Crk coupling promotes both cell invasion and suppression of apoptosis in 3D collagen matrices via Rac activation. Uncoupling CAS from Crk (by dominant-negative) induces apoptosis of invasive cells. ERK activation is a separate pathway that also supports invasion and survival. 3D collagen matrix invasion assay, apoptosis assay, dominant-negative expression, small GTPase inhibition The Journal of cell biology High 10747099
2000 Tyrosine-phosphorylated Wee1 interacts with the Crk SH2 domain in Xenopus egg extracts. Recombinant Wee1 restores apoptosis to SH2-interactor-depleted extracts, and Wee1-accelerated apoptosis requires endogenous Crk, placing Wee1-Crk complex upstream of apoptotic signaling. Cell-free Xenopus extract, immunodepletion, recombinant protein rescue, co-immunoprecipitation The Journal of cell biology High 11134069
2000 v-Crk constitutively activates the PI3K/AKT pathway in chicken embryo fibroblasts; both SH2 and SH3 domains are required. PI3K inhibitor LY294002 suppresses v-Crk-induced transformation, and constitutively active PI3K induces colony formation, establishing PI3K/AKT as an essential effector of v-Crk transformation. PI3K inhibitor treatment, dominant-active PI3K overexpression, AKT phosphorylation assay, transformation assay (colony formation) PNAS High 10852971
2000 v-Crk activates JNK via C3G and R-Ras (not Rap1): C3G activates R-Ras which then activates JNK via MLK3. Dominant-negative R-Ras blocks v-Crk-induced JNK activation and induces flat reversion of v-Crk-transformed cells. JNK reporter assay, dominant-negative GTPase expression, MLK3 inhibition, flat reversion assay The Journal of biological chemistry Medium 10777559
2001 Crk family adaptor proteins trans-activate c-Abl kinase: the CRK N-terminal SH3 domain interaction with c-Abl proline-rich motifs is required for both CRK phosphorylation by Abl and Abl activation by CRK. Phosphorylation of CRK Y221 negatively regulates this activation; the CRK C-terminal SH3 domain mediates c-Abl activation when Y221 is unphosphorylated. In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis Genes to cells High 11380621
2002 CrkII tyrosine 221 phosphorylation (Y221) regulates Rac membrane localization upon cell adhesion. CrkII-Y221F mutant shows enhanced binding to C3G and paxillin but fails to activate Rac signaling (JNK/PAK), membrane ruffle formation, or cell migration because it cannot promote Rac membrane translocation. Site-directed mutagenesis, co-immunoprecipitation, JNK/PAK activation assay, membrane fractionation, cell migration assay The EMBO journal High 12198159
2002 Crk SH2 domain contains a Crm1 (nuclear export factor) binding site within the C-terminal SH3 domain. A nuclear export sequence mutant of Crk (NES(-)) is retained in the nucleus, strongly binds Wee1 via its SH2 domain, and promotes apoptosis in mammalian cells. Co-immunoprecipitation with Crm1 and Wee1, nuclear localization experiments, apoptosis assay with NES mutant Molecular and cellular biology Medium 11839808
2002 Pseudomonas ExoT ADP-ribosylates Crk-I and Crk-II at Arg20 within the SH2 domain. ADP-ribosylation at Arg20 prevents Crk binding to p130CAS and paxillin, uncoupling integrin signaling and inhibiting Rac1-dependent functions. Mass spectrometry (site identification), GST pulldown, far Western, site-directed mutagenesis (R20K), Rac1 overexpression rescue The Journal of biological chemistry High 16123042
2003 Crk associates with a Paxillin/GIT2/β-PIX multimolecular complex. CrkII/CrkL overexpression promotes Rac-dependent relocalization of Paxillin to focal contacts; Paxillin mutants that cannot associate with Crk or GIT2 block Crk-dependent cell spreading and lamellipodia formation. Co-immunoprecipitation, dominant-negative Rac1, mutational analysis of paxillin, cell morphology and spreading assays Molecular biology of the cell Medium 12857867
2006 EphB4 receptor, stimulated by ephrin-B2, activates an Abl-Crk pathway that inhibits breast cancer cell viability, proliferation, motility, and invasion, and downregulates MMP-2. This pathway has constitutive activity in non-transformed mammary epithelial cells. Ephrin-B2 stimulation, Abl/Crk pathway inhibition, MMP-2 assay, cell viability/motility assays, xenograft model Nature cell biology Medium 16862147
2006 CRK adaptor protein is required for VEGFR-3 Y1063-dependent recruitment and activation of JNK1/2 via MKK4 for prosurvival signaling in endothelial cells. Systematic tyrosine mutation identified Y1063 as the direct CRK-I/II recruitment site. Systematic tyrosine mutant VEGFR-3 constructs, JNK activation assay, RNAi, specific JNK inhibitor Blood High 16076871
2006 GIT2 represses Crk- and Rac1-mediated lamellipodial extension and focal adhesion turnover. Knockdown of endogenous GIT2 induces cell migration, and this requires Crk as an essential downstream target (loss of Crk prevents GIT2 knockdown-induced migration). siRNA knockdown of GIT2, dominant-negative and rescue constructs, cell migration assay, focal adhesion analysis The EMBO journal Medium 16628223
2008 NK cell inhibitory receptor signaling induces tyrosine phosphorylation of CRK, causing CRK to dissociate from C3G and associate with c-Abl. Membrane-targeted tyrosine-mutant CRK overcomes NK cell inhibition, providing functional evidence that CRK phosphorylation is mechanistically required for inhibitory signaling. Co-immunoprecipitation, phospho-specific detection, membrane-targeted CRK mutant expression, NK cell cytotoxicity assay Immunity High 18835194
2008 Crk and CrkL are essential downstream effectors in the Reelin signaling pathway, acting downstream of Dab1 tyrosine phosphorylation. Conditional knockout of Crk and CrkL in neurons abolishes Reelin-induced C3G phosphorylation and Akt phosphorylation, but does not affect Dab1 phosphorylation/turnover (proximal Reelin signaling is intact). Cre-loxP conditional knockout, Reelin stimulation of cortical neurons, immunoblot for C3G and Akt phosphorylation The Journal of neuroscience High 19074029
2008 Crk family proteins are required for Reelin-induced dendritogenesis in hippocampal neurons. RNAi knockdown of Crk and CrkL blocks Reelin-enhanced dendritic complexity without affecting BDNF-induced dendritogenesis or axonogenesis, establishing pathway specificity. Retroviral RNAi, Reelin and BDNF stimulation, morphometric dendrite analysis Journal of cell science Medium 18477607
2009 CrkII and CrkL differentially activate Rac1 vs. Rap1: CrkII and CrkL (which possess a functional C-terminal SH3 domain) preferentially activate Rac1, whereas CrkI (lacking the C-terminal SH3 domain) preferentially activates Rap1. Crk adaptor activity is required for PDGF-stimulated actin remodeling and cell migration, and Abl kinase-mediated Crk phosphorylation terminates Crk signaling to promote focal adhesion turnover. RNAi/gene silencing, isoform-specific mutant rescue, small GTPase activation assays, PDGF stimulation, cell migration and focal adhesion analysis Journal of cell science High 19861495
2010 Dok-7 recruits Crk and CrkL to phosphorylated tyrosine residues in its C-terminal domain upon Agrin stimulation of MuSK. Selective inactivation of Crk and CrkL in skeletal muscle causes severe defects in neuromuscular synapse formation in vivo. Phosphorylation assay, co-immunoprecipitation, conditional knockout in skeletal muscle, NMJ morphology analysis Genes & development High 21041412
2011 CRK is a pro-apoptotic mediator of ER stress. CRK is cleaved during ER stress to generate an N-terminal ~14 kDa fragment. This fragment contains a BH3 domain that sensitizes mitochondria to cytochrome c release. Crk-/- cells are strongly resistant to ER-stress-induced apoptosis; mutation of the BH3 domain reduces apoptotic activity. Biochemical purification from ER-stressed cells, Crk-/- mouse cells, 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 receptor microclusters and F-actin network buildup, which are needed for CD16 activation signaling. Inhibitory receptor ligation (HLA-E/NKG2A) promotes central accumulation of phosphorylated Crk, preventing Crk-dependent actin network formation and blocking activation signals. Live imaging of primary NK cells on lipid bilayers, Crk-conditional knockout T/NK cells, F-actin staining, microcluster tracking Immunity High 22464172
2012 PAK1 phosphorylates CRK-II on serine 41. Phosphomimetic CRK-II S41 promotes cell motility and invasiveness and decreases p120-catenin; phosphodeficient S41 mutant reduces motility. RNAi silencing of PAK1 phenocopies the phosphodeficient mutant and is rescued by phosphomimetic CRK-II S41. Phosphomimetic/phosphodeficient CRK-II S41 mutants, PAK1 RNAi, wound healing and invasion assays, immunoblotting PloS one Medium 22848689
2015 Cyclophilin A (CypA) binds directly to CrkII at the Tyr221 phosphorylation site, sterically restricting access of Abl/EGFR kinases and suppressing CrkII phosphorylation. This keeps CrkII in the active (open) signaling state and promotes cell migration. Structural and biophysical data confirm the CypA-CrkII interaction. Structural studies, biophysical binding assays, phosphorylation assay, cell migration assay, cancer cell co-expression Nature chemical biology High 26656091
2015 CRK proteins coordinate with the RAP GEF C3G and adhesion docking molecule CASL to activate RAP1 and thereby regulate integrin-dependent T cell adhesion and chemotaxis. Conditional knockout of CRK and CRKL reduces integrin-dependent adhesion and prevents effector T cell trafficking to inflamed tissues but not lymphoid organ homing. Conditional knockout mice, integrin adhesion assay, chemotaxis assay, in vivo T cell trafficking, RAP1 activation assay The Journal of clinical investigation High 25621495
2018 Crk proteins transduce FGF signaling to promote lens fiber cell elongation. Genetic epistasis shows Crk and Crkl act downstream of FGF receptors; upon FGF stimulation, Crk proteins interact with Frs2, Shp2, and Grb2. Loss of Crk proteins can be partially compensated by activation of Ras and Rac signaling. Conditional knockout mouse, epistasis experiments (FGF pathway), co-immunoprecipitation (Frs2/Shp2/Grb2), Ras/Rac activation rescue eLife High 29360039
2018 Crk adaptor proteins mediate LFA-1 integrin outside-in signaling for actin polymerization and T cell migration. Crk-deficient T cells lack LFA-1-induced c-Cbl phosphorylation and its interaction with the PI3K subunit p85, thus impairing PI3K activity and cytoskeletal remodeling. Crk proteins are also required for mechanosensing (substrate stiffness-dependent spreading and CasL phosphorylation). Conditional knockout T cells, LFA-1 stimulation, c-Cbl/p85 co-immunoprecipitation, PI3K activity assay, traction force/stiffness substrates, CasL phosphorylation 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
2001 Crk family adaptors-signalling complex formation and biological roles. Oncogene 410 11607838
1990 Binding of transforming protein, P47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science (New York, N.Y.) 393 1694307
1995 Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas. Proceedings of the National Academy of Sciences of the United States of America 390 7479864
1994 c-Abl kinase regulates the protein binding activity of c-Crk. The EMBO journal 349 8194526
1994 Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes & development 316 7926767
1996 DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Molecular and cellular biology 290 8657152
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
2006 The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nature cell biology 250 16862147
2000 Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. The Journal of cell biology 238 10747099
2009 Crk and CrkL adaptor proteins: networks for physiological and pathological signaling. Cell communication and signaling : CCS 226 19426560
1993 Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 214 8361759
1994 SH2 and SH3 domains as molecular adhesives: the interactions of Crk and Abl. Trends in biochemical sciences 190 7855886
1994 CRK protein binds to two guanine nucleotide-releasing proteins for the Ras family and modulates nerve growth factor-induced activation of Ras in PC12 cells. Molecular and cellular biology 184 8035825
1999 Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades. The Journal of biological chemistry 178 10329689
1996 Stimulation through the T cell receptor induces Cbl association with Crk proteins and the guanine nucleotide exchange protein C3G. The Journal of biological chemistry 178 8626543
1990 Association of the v-crk oncogene product with phosphotyrosine-containing proteins and protein kinase activity. Proceedings of the National Academy of Sciences of the United States of America 171 1690891
1998 The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 158 9860979
2004 Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold. Biochimica et biophysica acta 154 15246680
1992 The product of the cellular crk gene consists primarily of SH2 and SH3 regions. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 152 1329926
2005 Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood 146 16076871
1996 Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes. The Journal of experimental medicine 145 8879209
2008 Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the Reelin pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 134 19074029
2000 v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation. Proceedings of the National Academy of Sciences of the United States of America 126 10852971
1991 Identification of domains of the v-crk oncogene product sufficient for association with phosphotyrosine-containing proteins. Molecular and cellular biology 123 1705010
1998 Physiological signals and oncogenesis mediated through Crk family adapter proteins. Journal of cellular physiology 116 10092207
2002 Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Molecular biology of the cell 103 12006644
1995 v-Crk modulation of growth factor-induced PC12 cell differentiation involves the Src homology 2 domain of v-Crk and sustained activation of the Ras/mitogen-activated protein kinase pathway. The Journal of biological chemistry 101 7657647
2010 Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L. Genes & development 94 21041412
2008 Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity 94 18835194
1997 Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood 93 9129019
1997 Enhancement of guanine-nucleotide exchange activity of C3G for Rap1 by the expression of Crk, CrkL, and Grb2. The Journal of biological chemistry 91 9268367
2000 Paxillin alpha and Crk-associated substrate exert opposing effects on cell migration and contact inhibition of growth through tyrosine phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 85 10922062
2002 Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Molecular biology of the cell 81 12475948
1995 Crk interacts with tyrosine-phosphorylated p116 upon T cell activation. The Journal of biological chemistry 80 7531694
1999 Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. Molecular and cellular biology 77 9891069
2003 Crk associates with a multimolecular Paxillin/GIT2/beta-PIX complex and promotes Rac-dependent relocalization of Paxillin to focal contacts. Molecular biology of the cell 76 12857867
2012 The adaptor protein Crk controls activation and inhibition of natural killer cells. Immunity 75 22464172
2006 Cardiovascular and craniofacial defects in Crk-null mice. Molecular and cellular biology 75 16880535
2008 Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis. Journal of cell science 74 18477607
1999 Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1 - Crk signaling complex formation. Oncogene 74 10618718
1996 B cell antigen receptor signaling induces the formation of complexes containing the Crk adapter proteins. The Journal of biological chemistry 70 8943292
2015 Calcium-dependent protein kinase (CDPK) and CDPK-related kinase (CRK) gene families in tomato: genome-wide identification and functional analyses in disease resistance. Molecular genetics and genomics : MGG 69 26520101
2002 Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling. The EMBO journal 68 12198159
1998 Activation of Rho-dependent cell spreading and focal adhesion biogenesis by the v-Crk adaptor protein. Molecular and cellular biology 66 9566923
2006 GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. The EMBO journal 65 16628223
1997 Role of Crk oncogene product in physiologic signaling. Critical reviews in oncogenesis 63 9622053
2002 v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras. Molecular and cellular biology 59 12242282
2000 Crk activation of JNK via C3G and R-Ras. The Journal of biological chemistry 58 10777559
1998 T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G. The Journal of biological chemistry 57 9497377
2006 Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines. Molecular cancer research : MCR 54 16849525
2002 Methamphetamine causes coordinate regulation of Src, Cas, Crk, and the Jun N-terminal kinase-Jun pathway. Molecular pharmacology 54 11961130
2001 Crk family adaptor proteins trans-activate c-Abl kinase. Genes to cells : devoted to molecular & cellular mechanisms 54 11380621
2000 CAS/Crk signalling mediates uptake of Yersinia into human epithelial cells. Cellular microbiology 53 11207607
2012 Crk adaptor proteins act as key signaling integrators for breast tumorigenesis. Breast cancer research : BCR 52 22569336
2000 A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein. Oncogene 52 11146548
2015 CRK proteins selectively regulate T cell migration into inflamed tissues. The Journal of clinical investigation 51 25621495
2006 Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS. Oncogene 51 16491127
2002 Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers. Cancer letters 50 11911970
1996 Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins. Oncogene 50 8700507
1996 A potential SH3 domain-binding site in the Crk SH2 domain. The Journal of biological chemistry 50 8702917
1997 Crk is required for apoptosis in Xenopus egg extracts. The EMBO journal 49 9029144
1996 Emerging components of the Crk oncogene product: the first identified adaptor protein. Cellular signalling 49 8911681
2003 Selective involvement of p130Cas/Crk/Pyk2/c-Src in endothelin-1-induced JNK activation. Hypertension (Dallas, Tex. : 1979) 47 12719447
2002 Novel function of Chat in controlling cell adhesion via Cas-Crk-C3G-pathway-mediated Rap1 activation. Journal of cell science 47 12432078
2009 Distinct roles for Crk adaptor isoforms in actin reorganization induced by extracellular signals. Journal of cell science 46 19861495
2019 Exosomes containing ErbB2/CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer. Cancer science 45 31141251
2012 Models of crk adaptor proteins in cancer. Genes & cancer 45 23226572
2002 Crk synergizes with epidermal growth factor for epithelial invasion and morphogenesis and is required for the met morphogenic program. The Journal of biological chemistry 44 12138161
2015 Members of the Plant CRK Superfamily Are Capable of Trans- and Autophosphorylation of Tyrosine Residues. The Journal of biological chemistry 42 25969537
2012 Roles for crk in cancer metastasis and invasion. Genes & cancer 42 23226571
2014 Mir-126 inhibits growth of SGC-7901 cells by synergistically targeting the oncogenes PI3KR2 and Crk, and the tumor suppressor PLK2. International journal of oncology 41 24969300
2009 Adaptor protein Crk induces Src-dependent activation of p38 MAPK in regulation of synovial sarcoma cell proliferation. Molecular cancer research : MCR 41 19737974
2021 Crk and CrkL as Therapeutic Targets for Cancer Treatment. Cells 40 33801580
2018 Crk adaptor proteins mediate actin-dependent T cell migration and mechanosensing induced by the integrin LFA-1. Science signaling 40 30538176
2017 Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer. Oncoimmunology 40 29296536
2012 PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells. PloS one 40 22848689
1997 v-Crk-induced cell transformation: changes in focal adhesion composition and signaling. Journal of cell science 40 9057091
2015 Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway. Nature chemical biology 38 26656091
2007 Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4. Biochemical and biophysical research communications 37 17825249
2006 Potential disease targets for drugs that disrupt protein-- protein interactions of Grb2 and Crk family adaptors. Current pharmaceutical design 37 16472145
2015 Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas. Medical oncology (Northwood, London, England) 36 25636509
2013 The adaptor protein Crk in immune response. Immunology and cell biology 36 24165979
2005 Uncoupling Crk signal transduction by Pseudomonas exoenzyme T. The Journal of biological chemistry 36 16123042
1999 Identification of a Drosophila homologue to vertebrate Crk by interaction with MBC. Gene 36 10072777
2018 Crk proteins transduce FGF signaling to promote lens fiber cell elongation. eLife 34 29360039
2018 Genome-Wide Identification and Functional Analyses of the CRK Gene Family in Cotton Reveals GbCRK18 Confers Verticillium Wilt Resistance in Gossypium barbadense. Frontiers in plant science 34 30254650
2004 Nck and Crk mediate distinct VEGF-induced signaling pathways that serve overlapping functions in focal adhesion turnover and integrin activation. Experimental cell research 34 15051508
2015 Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop. Cancer science 33 25816892
2011 Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 CRK-associated substrate. The Journal of biological chemistry 33 22084245
2004 Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers. Journal of human genetics 33 15138850
2004 A novel ERK-like, CRK-like protein kinase that modulates growth in Trypanosoma brucei via an autoregulatory C-terminal extension. Molecular microbiology 33 15387824
2013 Essential roles of Crk and CrkL in fibroblast structure and motility. Oncogene 32 24166500
2009 Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration. Cell research 32 19350053
2009 The role of Crk/Dock180/Rac1 pathway in the malignant behavior of human ovarian cancer cell SKOV3. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 20237902
2002 Apoptotic regulation by the Crk adapter protein mediated by interactions with Wee1 and Crm1/exportin. Molecular and cellular biology 32 11839808
2011 The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress. Nature cell biology 29 22179045
2000 Wee1-regulated apoptosis mediated by the crk adaptor protein in Xenopus egg extracts. The Journal of cell biology 29 11134069
1999 CCKA receptor activation stimulates p130(Cas) tyrosine phosphorylation, translocation, and association with Crk in rat pancreatic acinar cells. Biochemistry 29 9931015

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