The product of the cbl oncogene forms stable complexes in vivo with endogenous Crk in a tyrosine phosphorylation-dependent manner.
The cellular homologs of the v-Crk oncogene product are composed exclusively of Src homology region 2 (SH2) and SH3 domains. v-Crk overexpression in fibroblasts causes cell transformation and elevated tyrosine phosphorylation of specific cellular proteins. Among these proteins is a 130-kDa protein, identified as p130cas, that forms a stable complex in vivo with v-Crk. We have explored the role of endogenous Crk proteins in Bcr-Abl-transformed cells. In the K562 human chronic myelogenous leukemia cell line, p130cas is not tyrosine phosphorylated or bound to Crk. Instead, Crk proteins predominantly associate with the tyrosine-phosphorylated proto-oncogene product of Cbl. In vitro analysis showed that this interaction is mediated by the SH2 domain of Crk and can be inhibited with a phosphopeptide containing the Crk-SH2 binding motif. In NIH 3T3 cells transformed by Bcr-Abl, c-Cbl becomes strongly tyrosine phosphorylated and associates with c-Crk. The complex between c-Crk and c-Cbl is also seen upon T-cell receptor cross-linking or with the transforming, tyrosine-phosphorylated c-Cbl. These results indicate that Crk binds to c-Cbl in a tyrosine phosphorylation-dependent manner, suggesting a physiological role for the Crk-c-Cbl complex in Bcr-Abl tyrosine phosphorylation-mediated transformation.
Ribon
V
V
Department of Physiology, University of Michigan School of Medicine, Ann Arbor 48109, USA.
Hubbell
S
S
Herrera
R
R
Saltiel
A R
AR
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D050736:Oncogene Protein v-crk; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D011519:Proto-Oncogenes; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D014170:Transformation, Genetic; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains
C000715470:MAS1 protein, human; D050736:Oncogene Protein v-crk; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D016044:Fusion Proteins, bcr-abl; C067419:CBL protein, human; C493849:Cbl protein, mouse