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Gene Review

CRKL  -  v-crk avian sarcoma virus CT10 oncogene...

Homo sapiens

Synonyms: Crk-like protein
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Disease relevance of CRKL


High impact information on CRKL

  • The similarity between the Crkol-/- phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome [3].
  • In a trk-met-Gab1-specific branching morphogenesis assay, association of Gab1 with Shp2, but not PI(3)K, CRKL, or Shc was essential to induce a biological response in MDCK cells [6].
  • IC50(imatinib) is defined as the in vitro concentration of drug required to reduce phosphorylation of the adaptor protein Crkl by 50% [7].
  • IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like) [8].
  • Colocalization of DOCK2 with Crk-like (CrkL) and F-actin was shown by immunocytochemical analysis with the use of Jurkat cells [9].

Biological context of CRKL

  • In primary neutrophils from patients with CML, the major novel tyrosine-phosphorylated protein is CRKL, an SH2-SH3-SH3 linker protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene product [10].
  • Besides binding motifs for phosphatidylinositol 3-kinase and Grb2, Gab 1 contains multiple Tyr-X-X-Pro (YXXP) motifs which, when phosphorylated, are potential binding sites for the adapter proteins c-Crk and Crk-like (CRKL) [11].
  • Constitutive phosphorylation of CRKL is unique to CML, indicating that it may be a useful target for therapeutic intervention [1].
  • Knockdown of RIN1 in epithelial-cell lines blocked the induction of CRKL phosphorylation, confirming that RIN1 normally functions as an inhibitor of cell motility [12].
  • We identified one SH2 and two SH3 domains within the 303 amino acid open reading frame of this crk-like gene, CRKL [13].

Anatomical context of CRKL

  • However, in the lymphoid H9 cell line, the major tyrosine-phosphorylated CRKL-binding protein was p110(HEF1) [14].
  • Several other phosphoproteins were also detected in anti-CRKL immunoprecipitates, one of which has been identified as paxillin, a 68-kDa focal adhesion protein which we have previously shown to be phosphorylated by p210BCR/ABL [10].
  • Additionally, CRKL is involved in signaling initiated by crosslinking of beta integrins, and B cell or T cell receptors [15].
  • In Ph- peripheral blood cells, CRKL is present only in the nonphosphorylated form [4].
  • Here we report that CRKL is phosphorylated when overexpressed, activates RAS and JUN kinase signaling pathways, and transforms fibroblasts in a RAS-dependent fashion [16].

Associations of CRKL with chemical compounds

  • Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1) [14].
  • In primary leukemic neutrophils from patients with CML, the major tyrosine phosphorylated protein is CRKL, an SH2-SH3-SH3 adapter protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene [17].
  • Far Western blotting with a CRKL-SH3 glutathione S-transferase fusion protein showed that CRKL binds directly to p85(PI3K )in vitro [18].
  • In cells expressing the proline deletion mutation of BCR-ABL, CRKL is still tyrosine phosphorylated and forms a complex with BCR-ABL as demonstrated by coimmunoprecipitation [19].
  • Thus, we suggest that del22q11 is a contiguous gene syndrome involving dose-sensitive interaction of CRKL and TBX1 and locally aberrant RA signaling [20].

Physical interactions of CRKL


Enzymatic interactions of CRKL

  • Within this region, mutation of tyrosine residue 207 yielded a mutant CRKL which could not be phosphorylated by BCR/ABL [23].
  • In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells [24].

Other interactions of CRKL

  • Anti-CRKL immunoprecipitates from CML cells, but not normal cells, were found to contain p210BCR/ABL and c-ABL [10].
  • These results suggest that the p210BCR/ABL oncogene may be physically linked to the focal adhesion-associated protein paxillin in hematopoietic cells by CRKL [10].
  • CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II [15].
  • In two hematopoietic cell lines, MO7e and H9, we found that CRKL rapidly associates with tyrosine-phosphorylated proteins after cross-linking of beta1 integrins with fibronectin or anti-beta1 integrin monoclonal antibodies [14].
  • Stimulation of human embryonic kidney cells (HEK293) with HGF leads to Gab1 association with CRKL [11].

Analytical, diagnostic and therapeutic context of CRKL

  • CRKL binds via its first SH3 domain to several downstream signal transducers, including C3G an activator of the small GTPase Rap1 [11].
  • In vitro complexes were highly stable and in vivo complexes of c-Crk and CRKL with HPK1 were detectable by co-immunoprecipitation with transiently transfected cells but also with endogenous proteins [25].
  • Immunoblotting with anti-CRKL antibodies showed the presence of CRKL protein in CML cells and cell lines as well as in antiphosphotyrosine immunoprecipitates from CML cells [1].
  • Our data suggest that the interaction between CRKL and the proline deletion mutant of BCR-ABL is an indirect interaction as CRKL does not interact directly with the proline deletion mutant of BCR-ABL in a gel overlay assay or in a yeast two-hybrid assay [19].


  1. Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. Nichols, G.L., Raines, M.A., Vera, J.C., Lacomis, L., Tempst, P., Golde, D.W. Blood (1994) [Pubmed]
  2. Physiological signals and oncogenesis mediated through Crk family adapter proteins. Feller, S.M., Posern, G., Voss, J., Kardinal, C., Sakkab, D., Zheng, J., Knudsen, B.S. J. Cell. Physiol. (1998) [Pubmed]
  3. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome. Guris, D.L., Fantes, J., Tara, D., Druker, B.J., Imamoto, A. Nat. Genet. (2001) [Pubmed]
  4. Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. ten Hoeve, J., Arlinghaus, R.B., Guo, J.Q., Heisterkamp, N., Groffen, J. Blood (1994) [Pubmed]
  5. Inhibition of Grb2 and Crkl proteins results in growth inhibition of Philadelphia chromosome positive leukemic cells. Tari, A.M., Arlinghaus, R., Lopez-Berestein, G. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  6. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. Schaeper, U., Gehring, N.H., Fuchs, K.P., Sachs, M., Kempkes, B., Birchmeier, W. J. Cell Biol. (2000) [Pubmed]
  7. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. White, D.L., Saunders, V.A., Dang, P., Engler, J., Zannettino, A.C., Cambareri, A.C., Quinn, S.R., Manley, P.W., Hughes, T.P. Blood (2006) [Pubmed]
  8. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. White, D., Saunders, V., Lyons, A.B., Branford, S., Grigg, A., To, L.B., Hughes, T. Blood (2005) [Pubmed]
  9. DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines. Nishihara, H., Maeda, M., Oda, A., Tsuda, M., Sawa, H., Nagashima, K., Tanaka, S. Blood (2002) [Pubmed]
  10. CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. Salgia, R., Uemura, N., Okuda, K., Li, J.L., Pisick, E., Sattler, M., de Jong, R., Druker, B., Heisterkamp, N., Chen, L.B. J. Biol. Chem. (1995) [Pubmed]
  11. Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. Sakkab, D., Lewitzky, M., Posern, G., Schaeper, U., Sachs, M., Birchmeier, W., Feller, S.M. J. Biol. Chem. (2000) [Pubmed]
  12. RIN1 is an ABL tyrosine kinase activator and a regulator of epithelial-cell adhesion and migration. Hu, H., Bliss, J.M., Wang, Y., Colicelli, J. Curr. Biol. (2005) [Pubmed]
  13. Isolation and chromosomal localization of CRKL, a human crk-like gene. ten Hoeve, J., Morris, C., Heisterkamp, N., Groffen, J. Oncogene (1993) [Pubmed]
  14. Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1). Sattler, M., Salgia, R., Shrikhande, G., Verma, S., Uemura, N., Law, S.F., Golemis, E.A., Griffin, J.D. J. Biol. Chem. (1997) [Pubmed]
  15. Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. Sattler, M., Salgia, R. Leukemia (1998) [Pubmed]
  16. The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCR-ABL oncogene. Senechal, K., Halpern, J., Sawyers, C.L. J. Biol. Chem. (1996) [Pubmed]
  17. The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins. Uemura, N., Salgia, R., Li, J.L., Pisick, E., Sattler, M., Griffin, J.D. Leukemia (1997) [Pubmed]
  18. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL). Sattler, M., Salgia, R., Shrikhande, G., Verma, S., Pisick, E., Prasad, K.V., Griffin, J.D. J. Biol. Chem. (1997) [Pubmed]
  19. Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Heaney, C., Kolibaba, K., Bhat, A., Oda, T., Ohno, S., Fanning, S., Druker, B.J. Blood (1997) [Pubmed]
  20. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Guris, D.L., Duester, G., Papaioannou, V.E., Imamoto, A. Dev. Cell (2006) [Pubmed]
  21. CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling. Park, R.K., Kyono, W.T., Liu, Y., Durden, D.L. J. Immunol. (1998) [Pubmed]
  22. Structural requirements for function of the Crkl adapter protein in fibroblasts and hematopoietic cells. Senechal, K., Heaney, C., Druker, B., Sawyers, C.L. Mol. Cell. Biol. (1998) [Pubmed]
  23. Tyrosine 207 in CRKL is the BCR/ABL phosphorylation site. de Jong, R., ten Hoeve, J., Heisterkamp, N., Groffen, J. Oncogene (1997) [Pubmed]
  24. The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways. Voss, J., Posern, G., Hannemann, J.R., Wiedemann, L.M., Turhan, A.G., Poirel, H., Bernard, O.A., Adermann, K., Kardinal, C., Feller, S.M. Oncogene (2000) [Pubmed]
  25. The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oehrl, W., Kardinal, C., Ruf, S., Adermann, K., Groffen, J., Feng, G.S., Blenis, J., Tan, T.H., Feller, S.M. Oncogene (1998) [Pubmed]
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