Crk family adaptor proteins trans-activate c-Abl kinase.
BACKGROUND
c-Abl kinase is activated in response to a variety of biological stimuli. Crk family adaptor proteins can interact physically with c-Abl and be involved in the activation of c-Abl kinase.


RESULTS
We report that the Crk family of adaptor proteins act as trans-acting activators of c-Abl kinase. The interaction of the amino-terminal Src-homology (SH) 3 domain of c-Crk and the proline-rich motifs of c-Abl is an essential step for the phosphorylation of c-Crk by c-Abl, as well as the activation of c-Abl by c-Crk. The activation of c-Abl by c-Crk is negatively regulated by phosphorylation of the tyrosine 221 of c-Crk. Our data suggest that, in the absence of phosphorylation of the tyrosine Y221, the SH2 domain of c-Crk becomes free to bind to target molecules while the carboxyl-terminal SH3 domain of c-Crk binds to the proline-rich region of c-Abl, inducing the activation of c-Abl by c-Crk.


CONCLUSIONS
This study suggests that the Crk family functions as trans-acting activators of c-Abl kinase. The phosphorylation of c-Crk may regulate c-Abl kinase.
Shishido
T
T
Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan.
Akagi
T
T
Chalmers
A
A
Maeda
M
M
Terada
T
T
Georgescu
M M
MM
Hanafusa
H
H
D000818:Animals; D001665:Binding Sites; D002461:Cell Line, Transformed; D002642:Chick Embryo; D005347:Fibroblasts / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D050736:Oncogene Protein v-crk; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics*
D050736:Oncogene Protein v-crk; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D015682:Retroviridae Proteins, Oncogenic; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl