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J. Biol. Chem., Vol. 279, Issue 23, 24899-24905, June 4, 2004

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Mitogen-induced Rapid Phosphorylation of Serine 795 of the Retinoblastoma Gene Product in Vascular Smooth Muscle Cells Involves ERK Activation^*

Maria N. Garnovskaya, Yurii V. Mukhin, Tamara M. Vlasova, Jasjit S. Grewal, Michael E. Ullian, Baby G. Tholanikunnel, and John R. Raymond

From the Medical and Research Services of the Ralph H. Johnson Veterans Affairs Medical Center and Department of Medicine (Nephrology Division) of the Medical University of South Carolina, Charleston, South Carolina 29425

We examined the relationship between mitogen-activated MEK (mitogen and extracellular signal-regulated protein kinase kinase) and phosphorylation of the gene product encoded by retinoblastoma (hereafter referred to as Rb) in vascular smooth muscle cells. Brief treatment of the cells with 100 nM angiotensin II or 1 µM serotonin resulted in serine phosphorylation of Rb that was equal in magnitude to that induced by treating cells for 20 h with 10% fetal bovine serum (3 x basal). There was no detectable rapid phosphorylation of two close cousins of Rb, p107 and p130. Phosphorylation state-specific antisera demonstrated that the rapid phosphorylation occurred on Ser⁷⁹⁵, but not on Ser²⁴⁹, Thr²⁵², Thr³⁷³, Ser⁷⁸⁰, Ser⁸⁰⁷, or Ser⁸¹¹. Phosphorylation of Rb Ser⁷⁹⁵ peaked at 10 min, lagging behind phosphorylation of MEK and ERK (extracellular signal-regulated protein kinase). Rb Ser⁷⁹⁵ phosphorylation could be blocked by PD98059, a MEK inhibitor, and greatly attenuated by apigenin, an inhibitor of the Ras Raf MEK ERK pathway. The effect also appears to be mediated by CDK4. Immunoprecipitation/immunoblot studies revealed that serotonin and angiotensin II induced complex formation between CDK4, cyclin D1, and phosphorylated ERK. These studies show a rapid, novel, and selective phosphorylation of Rb Ser⁷⁹⁵ by mitogens and demonstrate an unexpected rapid linkage between the actions of the Ras Raf MEK ERK pathway and the phosphorylation state of Rb.

Received for publication, October 23, 2003 , and in revised form, April 2, 2004.

^* This work was supported by Department of Veterans Affairs Merit Awards (to M. N. G. and J. R. R.) and a Research Enhancement Award Program (to J. R. R., Y. V. M., and M. N. G.), National Institutes of Health Grants RO1-DK52448 and RO1-GM63909 (to J. R. R.) and K01-DK02694 (to Y. V. M.), American Heart Association grants (to Y. V .M., J. S. G., and M. E. U.), a laboratory endowment jointly supported by the M.U.S.C. Division of Nephrology and Dialysis Clinics, Inc. (to J. R. R.), and a M.U.S.C. University Research Foundation award (to M. N. G.). 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.

To whom correspondence should be addressed: Medical University of South Carolina, 96 Jonathan Lucas St., Rm. 829 CSB, P. O. Box 250623, Charleston, SC 29425-2227. Tel.: 843-876-5128 or 843-789-6774; Fax: 843-876-5129 or 843-792-8399; E-mail: garnovsk{at}musc.edu.

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