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J Biol Chem, Vol. 273, Issue 24, 14780-14787, June 12, 1998
, and
From the Diabetes Branch, NIDDK, National Institutes of Health,
Bethesda, Maryland 20892 and the The closely related proto-oncogene proteins CrkII
and CrkL consist of one SH2 and two SH3 domains and share 60% overall
homology with the highest identity within their functional domains. In this study we show that CrkL and CrkII may play overlapping but different roles in insulin-like growth factor (IGF)-I receptor-mediated signal transduction. While both proteins are substrates involved in
IGF-I receptor signaling, they apparently demonstrate important different properties and different biological responses. Evidence supporting this hypothesis includes (a) the oncogenic
potential of CrkL versus the absence of this potential in
CrkII overexpressing cell lines, (b) the inhibition of
IGF-I-dependent cell cycle progression by overexpression of
CrkII, and (c) the differential regulation of the
phosphorylation status of selective proteins in CrkII and CrkL
overexpressing cell lines. In addition we demonstrate the specific
association of CrkL and CrkII with the newly characterized IRS-4
protein, again in a differential manner. Whereas CrkL strongly interacts with IRS-4 via its SH2 and N-terminal SH3 domains, CrkII interacts only via its SH2 domain, possibly explaining the unstable nature of IRS-4-CrkII association. The results obtained allow us to
propose a unique mechanism of CrkL and CrkII tyrosine phosphorylation in response to IGF-I stimulation. Thus these highly homologous proteins
apparently possess structural features that allow for the differential
association of each protein with different effector molecules, thereby
activating different signaling pathways and resulting in unique
biological roles of these proteins.
Department of Molecular
and Cell Biology, the Weizmann Institute of Science,
Rehovot 76100, Israel
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