Adapter molecule crk

Function

Adapter molecule crk is a member of an adapter protein family that binds to several tyrosine-phosphorylated proteins. This protein has several SH2 and SH3 domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of tyrosine kinase through SH2-phosphotyrosine interaction. The N-terminal SH2 domain of this protein functions as a positive regulator of transformation whereas the C-terminal SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described.

Crk together with CrkL participates in the Reelin signaling cascade downstream of DAB1.

v-Crk, a transforming oncoprotein from avian sarcoma viruses, is a fusion of viral "gag" protein with the SH2 and SH3 domains of cellular Crk. The name Crk is from "CT10 Regulator of Kinase" where CT10 is the avian virus from which was isolated a protein, lacking kinase domains, but capable of stimulating phosphorylation of tyrosines in cells.

Crk should not be confused with Src, which also has cellular (c-Src) and viral (v-Src) forms and is involved in some of the same signaling pathways but is a protein tyrosine-kinase.

Interactions

CRK (gene) has been shown to interact with:

• BCAR1,
• Cbl gene,
• Dock180,
• EPS15,
• Epidermal growth factor receptor,
• Grb2,
• IRS4,
• MAP4K1,
• MAPK8,
• NEDD9,
• PDGFRA,
• PDGFRB,
• PTK2,
• Paxillin
• RAPGEF1,
• RICS,
• SH3KBP1, and
• SOS1.

References

References

1. (1990). "Association of the v-crk oncogene product with phosphotyrosine-containing proteins and protein kinase activity.". Proc Natl Acad Sci U S A.
2. (June 2008). "Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis". J. Cell Sci..
3. (December 2008). "Crk and Crk-like play essential overlapping roles downstream of disabled-1 in the Reelin pathway". J. Neurosci..
4. "Entrez Gene: CRK v-crk sarcoma virus CT10 oncogene homolog (avian)".
5. (1996). "Direct Binding of C-terminal Region of p130Graphic to SH2 and SH3 Domains of Src Kinase". J. Biol. Chem..
6. (March 1988). "A novel viral oncogene with structural similarity to phospholipase C". Nature.
7. (2004). "The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity". Cancer Res..
8. (2004). "P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading". Mol. Biol. Cell.
9. (2003). "Differential regulation of cell motility and invasion by FAK". J. Cell Biol..
10. (2001). "Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway". J. Biol. Chem..
11. (1999). "Regulation of fibroblast motility by the protein tyrosine phosphatase PTP-PEST". J. Biol. Chem..
12. (1999). "Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts". J. Cell Biol..
13. (1998). "Inhibition of p130cas tyrosine phosphorylation by calyculin A". J. Leukoc. Biol..
14. (1999). "Adaptor proteins Grb2 and Crk couple Pyk2 with activation of specific mitogen-activated protein kinase cascades". J. Biol. Chem..
15. (2000). "Stromal cell-derived factor-1alpha stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C". Blood.
16. (1998). "Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells". J. Biol. Chem..
17. (1997). "CSF-1 stimulation induces the formation of a multiprotein complex including CSF-1 receptor, c-Cbl, PI 3-kinase, Crk-II and Grb2". Oncogene.
18. (1999). "Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins". Biochim. Biophys. Acta.
19. (1996). "DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane". Mol. Cell. Biol..
20. (1995). "The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R". J. Biol. Chem..
21. (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol..
22. (1998). "Phosphorylation of CrkII adaptor protein at tyrosine 221 by epidermal growth factor receptor". J. Biol. Chem..
23. (2000). "The beta-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis". Biochem. J..
24. (1996). "Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins". J. Biol. Chem..
25. (1996). "Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor". J. Biol. Chem..
26. (2001). "The insulin-like growth factor I receptor-induced interaction of insulin receptor substrate-4 and Crk-II". Endocrinology.
27. (1998). "Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction". J. Biol. Chem..
28. (1998). "The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins". Oncogene.
29. (1999). "Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase". Mol. Cell. Biol..
30. (2001). "Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling". J. Biol. Chem..
31. (2001). "A direct interaction between JNK1 and CrkII is critical for Rac1-induced JNK activation". EMBO J..
32. (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". J. Exp. Med..
33. (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". J. Biol. Chem..
34. (1998). "Identification of Tyr-762 in the platelet-derived growth factor alpha-receptor as the binding site for Crk proteins". Oncogene.
35. (2000). "Differential interaction of CrkII adaptor protein with platelet-derived growth factor alpha- and beta-receptors is determined by its internal tyrosine phosphorylation". Biochem. Biophys. Res. Commun..
36. (2002). "Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling". EMBO J..
37. (1994). "C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins". Proc. Natl. Acad. Sci. U.S.A..
38. (2003). "GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2". J. Biol. Chem..
39. (2003). "Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP". J. Biol. Chem..
40. (2000). "Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes". Biochem. Biophys. Res. Commun..