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J. Biol. Chem., Vol. 278, Issue 39, 37064-37072, September 26, 2003

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Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts^*,

Chang Shin Park, Ian C. Schneider  and Jason M. Haugh 

From the Department of Chemical Engineering, North Carolina State University, Raleigh, North Carolina 27695-7905

Isoforms of the serine-threonine kinase Akt coordinate multiple cell survival pathways in response to stimuli such as platelet-derived growth factor (PDGF). Activation of Akt is a multistep process, which relies on the production of 3'-phosphorylated phosphoinositide (PI) lipids by PI 3-kinases. To quantitatively assess the kinetics of PDGF receptor/PI 3-kinase/Akt signaling in fibroblasts, a systematic study of this pathway was performed, and a mechanistic mathematical model that describes its operation was formulated. We find that PDGF receptor phosphorylation exhibits positive cooperativity with respect to PDGF concentration, and its kinetics are quantitatively consistent with a mechanism in which receptor dimerization is initially mediated by the association of two 1:1 PDGF/PDGF receptor complexes. Receptor phosphorylation is transient at high concentrations of PDGF, consistent with the loss of activated receptors upon endocytosis. By comparison, Akt activation responds to lower PDGF concentrations and exhibits more sustained kinetics. Further analysis and modeling suggest that the pathway is saturated at the level of PI 3-kinase activation, and that the p110 catalytic subunit of PI 3-kinase contributes most to PDGF-stimulated 3'-PI production. Thus, at high concentrations of PDGF the kinetics of 3'-PI production are limited by the turnover rate of these lipids, while the Akt response is additionally influenced by the rate of Akt deactivation.

Received for publication, May 12, 2003 , and in revised form, July 18, 2003.

^* This work was supported by grants from the NSF Biotechnology Program (BES-0111434) and the Whitaker Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplementary data.

Supported by a fellowship from the Department of Education GAANN Program.

To whom correspondence should be addressed: Box 7905, North Carolina State University, Raleigh, NC 27695. Tel.: 919-513-3851; Fax: 919-515-3465; E-mail: jason_haugh{at}ncsu.edu.

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