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(Received for publication, June 18, 1996, and in revised form, August 8, 1996)
From the Department of Physiology, University of Michigan,
Ann Arbor, Michigan 48109-0622
Cholecystokinin (CCK) has recently been shown to
activate the mitogen-activated protein kinase (MAPK) cascade
(Ras-Raf-MAPK kinase-MAPK) in pancreatic acini. The mechanism by which
the Gq protein-coupled CCK receptor activates Ras, however,
is currently unknown. Growth factor receptors are known to activate Ras
by means of adaptor proteins that bind to phosphotyrosine domains. We
therefore compared the effects of CCK and epidermal growth factor (EGF)
on Tyr phosphorylation of the adaptor proteins Shc and its association
with Grb2 and the guanine nucleotide exchange factor SOS. Three major
isoforms of Shc (p46, p52, p66) were detected in isolated rat
pancreatic acini with p52 Shc being the predominant form. CCK and EGF
increased tyrosyl phosphorylation of Shc (251 and 337% of control,
respectively). CCK-stimulated tyrosyl phosphorylation of Shc as well as
Shc-Grb2 complex formation was significant at 2.5 min, maximal at 5 min, and persisted for at least 30 min. Finally, SOS was found to be
associated with Grb2 as assessed by probing of anti-Grb2
immunoprecipitates with anti-SOS. Since MAPK in pancreatic acini is
activated via protein kinase C (PKC), we studied the effect of phorbol
esters on Shc phosphorylation and found
12-O-tetradecanoylphorbol-13-acetate to be as potent as
CCK. Furthermore, GF-109203X, a PKC inhibitor, abolished the effect of
12-O-tetradecanoylphorbol-13-acetate and also the effect of
CCK but not the effect of EGF on Shc tyrosyl phosphorylation.
CCK-induced tyrosyl phosphorylation of Shc was found to be
phosphatidylinositol 3-kinase-independent, and CCK did not cause EGF
receptor activation. These results suggest that formation of an
Shc-Grb2-SOS complex via a PKC-dependent mechanism may
provide the link between Gq protein-coupled CCK receptor
stimulation and Ras activation in these cells.
Volume 271, Number 43,
Issue of October 25, 1996
pp. 27125-27129
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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