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J. Biol. Chem., Vol. 278, Issue 36, 34548-34554, September 5, 2003

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Adhesion-dependent Activation of the ERK1/2 Cascade Is By-passed in Melanoma Cells^*

Sean R. Conner , Glynis Scott  and Andrew E. Aplin  ¶

From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208 and the Department of Dermatology, University of Rochester School of Medicine, Rochester, New York 14642

Normal cells are dependent upon integrin-mediated adhesion to the extracellular matrix for cell proliferation and survival. Integrins regulate these processes partially through control of extracellular signal-regulated kinases 1 and 2 (ERK1/2). A trait of malignant cells is their ability to undergo anchorage-independent growth. Melanomas are tumors arising from normal melanocytes that, if undetected at an early stage, are highly invasive and poorly treatable. Proliferation of melanoma cells and melanocytes is dependent upon ERK1/2 signaling, and mutation of B-Raf, a component of the ERK1/2 pathway, is commonly found in melanomas. We addressed the role of integrin-mediated adhesion in ERK1/2 signaling in human melanoma cells and primary melanocytes. Basal ERK1/2 activity was low, and growth factor activation was adhesion-dependent in normal human melanocytes. By contrast in mutant B-Raf-expressing melanoma cells (SK-MEL-24 and SK-MEL-28), the ERK1/2 pathway was constitutively active, and adhesion-dependent regulation of ERK1/2 activity was by-passed. Furthermore, in melanoma cells, ERK1/2 translocated to the nucleus and regulated transcription events in an adhesion-independent manner. Expression of mutant V599E B-Raf in normal melanocytes was sufficient to promote adhesion-independent ERK1/2 signaling. These results indicate that alterations in the adhesion requirement for ERK1/2 signaling in melanocytes are associated with the acquisition of malignant cell behavior.

Received for publication, June 3, 2003

^* 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: MS 441, Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave., MC-165, Albany, NY 12208. Tel.: 518-262-5700; Fax: 518-262-5669; E-mail: aplina{at}mail.amc.edu.

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