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J Biol Chem, Vol. 275, Issue 18, 13377-13385, May 5, 2000
,
From the Douglas Hospital Research Center, Departments of
Psychiatry and of Pharmacology and Therapeutics, McGill University,
Montreal, Quebec H4H 1R3, Canada
Activation of protein kinase C (PKC) plays an
important role in the negative regulation of receptor signaling, but
its effect on insulin-like growth factor-1 (IGF-1) receptor signaling
remains unclear. In this study, we characterized the intracellular
pathways involved in IGF-1-induced activation of Akt and evaluated the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on
the Akt activation by IGF-1. IGF-1 induced a time- and
concentration-dependent activation of Akt. The effect of
IGF-1 was blocked by the phosphatidylinositide 3-kinase (PI3K)
inhibitors LY294002 (50 µM) and wortmannin (0.5 µM), but not by the MEK inhibitor PD98059 (50 µM) or the p70 S6 kinase pathway inhibitor rapamycin (50 nM), suggesting that the stimulation of Akt by IGF-1 is
mediated by the PI3K pathway. Interestingly, cotreatment with PMA (400 nM) attenuated IGF-1-induced activation of Akt. The
attenuation was blocked completely by the PKC inhibitor GO6983 (0.5 µM), but only partially by the MEK inhibitor PD98059 (50 µM), indicating that MAPK-dependent and
-independent pathways are involved. PMA induced the activation of PKC
in PC12 cells, and this induction was blocked by GO6983. These data
further support the role of PKC in the effect of PMA. Moreover, PKC
is likely involved in the action of PMA on the basis of data obtained
using isoform-specific inhibitors such as rottlerin. PMA also decreased IGF-1-induced tyrosine phosphorylation of insulin receptor substrate-1 and its association with PI3K. Taken together, these results suggest, for the first time, that stimulation of PKC modulates IGF-1-induced activation of Akt.
Recipient of a doctoral fellowship from the Fonds pour la
Formation de Chercheurs et l'Aide à la Recherche.
§
Chercheur-Boursier Junior II of the Fonds de la Recherche en
Santé du Quebec.
¶
Chercheur-Boursier de Merite Exceptionel of the Fonds de la
Recherche en Santé du Quebec. To whom correspondence and reprint requests should be addressed: Douglas Hospital Research Center, 6875 LaSalle Blvd., Verdun, Quebec H4H 1R3, Canada. Tel.: 514-762-3048; Fax:
514-762-3034; E-mail: mcou@musica.mcgill.ca.
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