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J. Biol. Chem., Vol. 279, Issue 46, 47808-47814, November 12, 2004

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Phosphorylation Regulates KSR1 Stability, ERK Activation, and Cell Proliferation^*

Gina L. Razidlo¶, Robert L. Kortum, Jamie L. Haferbier, and Robert E. Lewis||

From the Eppley Institute for Research in Cancer and Allied Diseases and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696

Kinase suppressor of Ras (KSR) is a molecular scaffold that interacts with the components of the Raf/MEK/ERK kinase cascade and positively regulates ERK signaling. Phosphorylation of KSR1, particularly at Ser³⁹², is a critical regulator of KSR1 subcellular localization and ERK activation. We examined the role of phosphorylation of both Ser³⁹² and Thr²⁷⁴ in regulating ERK activation and cell proliferation. We hypothesized that KSR1 phosphorylation is involved in generating signaling specificity through the Raf/MEK/ERK kinase cascade in response to stimulation by different growth factors. In fibroblasts, platelet-derived growth factor stimulation induces sustained ERK activation and promotes S-phase entry. Treatment with epidermal growth factor induces transient ERK activation but fails to drive cells into S phase. Mutation of Ser³⁹² and Thr²⁷⁴ (KSR1.TVSA) promotes sustained ERK activation and cell cycle progression with either platelet-derived growth factor or epidermal growth factor treatment. KSR1^–/– mouse embryo fibroblasts expressing KSR1.TVSA proliferate two times faster and grow to a higher density than cells expressing the same level of wild-type KSR1. In addition, KSR1.TVSA is more stable than wild-type KSR1. These data demonstrate that phosphorylation and stability of the molecular scaffold KSR1 are critical regulators of growth factor-specific responses that promote cell proliferation.

Received for publication, June 8, 2004 , and in revised form, August 24, 2004.

^* This research was supported by National Institutes of Health Grants CA90400 and CA36727. 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 a supplementary figure showing fluorescent photomicrographs of anti-BrdUrd- and 4',6-diamidino-2-phenylindole-stained cells.

^¶ Supported by a predoctoral fellowship from the National Science Foundation.

^|| To whom correspondence should be addressed: Eppley Institute, University of Nebraska Medical Center, 987696 Nebraska Medical Center, Omaha, NE 68198-7696. Tel.: 402-559-8290; Fax: 402-559-3739; E-mail: rlewis{at}unmc.edu.

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