INTERPLAY OF THE PROTOONCOGENE PROTEINS CRKL AND CRKII IN INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR-MEDIATED SIGNAL-TRANSDUCTION

The closely related proto-oncogene proteins CrkII and CrkL consist of cane SH2 and two SI43 domains and share 60% overall homology with the highest identity within their functional domains. In this study we sho w that CrkL and CrkII may play overlapping but different roles in insu lin-like growth factor (IGF)-I receptor-mediated signal transduction. While both proteins are substrates involved in IGF-I receptor signalin g, they apparently demonstrate important different properties and diff erent biological responses. Evidence supporting this hypothesis includ es (a) the oncogenic potential of CrkL versus the absence of this pote ntial in CrkII overexpressing cell lines, (b) the inhibition of IGF-I- dependent cell cycle progression by overexpression of CrkII, and (c) t he differential regulation of the phosphorylation status of selective proteins in CrkII and CrkL overexpressing cell lines. In addition we d emonstrate the specific association of CrkL and CrkII with the newly c haracterized IRS-4 protein, again in a differential manner. Whereas Cr kL strongly interacts with IRS-4 via its SH2 and N-terminal SH3 domain s, CrkII interacts only via its SH2 domain, possibly explaining the un stable nature of IRS-4-CrkII association. The results obtained snow us to propose a unique mechanism of CrkL and CrkII tyrosine phosphorylat ion in response to IGF-I stimulation. Thus these highly homologous pro teins apparently possess structural features that allow for the differ ential association of each protein with different effector molecules, thereby activating different signaling pathways and resulting in uniqu e biological roles of these proteins.