Platelet-derived Growth Factor and Fibronectin-stimulated Migration Are Differentially Regulated by the Rac and Extracellular Signal-regulated Kinase Pathways*
- Bela Anand-Apte‡§,
- Bruce R. Zetter‡,
- Akila Viswanathan‡,
- Rong-Guo Qiu¶,
- Jing Chen¶,
- Rosamaria Ruggieri¶ and
- Marc Symons¶‖
- From the ‡Departments of Surgery and Cell Biology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 and ¶ONYX Pharmaceuticals, Richmond, California 94806
Abstract
Directed cell migration is essential for a variety of important biological processes ranging from development and angiogenesis to metastasis. Ras plays a pivotal role in the signaling cascade that governs chemotaxis of fibroblasts toward platelet-derived growth factor-BB (PDGF-BB). Ras activates multiple downstream pathways, which include the extracellular signal-regulated kinase (ERK), Rac, and Ral signaling cascades. We therefore investigated the role of the Rac and ERK pathways in cell migration. We showed that migration of fibroblasts toward PDGF-BB is inhibited by expression of dominant negative Asn-17 Rac1. Blocking of the ERK pathway by either expression of dominant negative Ala-218/Ala-222-mitogen-activated protein kinase kinase (A218/A222-MEK1) or by a MEK-specific inhibitor did not inhibit migration toward PDGF-BB. In contrast, migration toward soluble fibronectin was suppressed by inhibition of the ERK pathway but not by Asn-17 Rac1 expression. These results indicate that directed cell migration mediated by different receptor classes in response to different ligands differentially utilizes the Rac and ERK pathways and suggest that Rac might play a critical role in pathological processes such as angiogenesis and metastasis.
Footnotes
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↵* The research was supported by National Institutes of Health Grant CA37393 (to B. R. Z.) and was carried out with interactive support by Bayer Corp.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ Present address: Dept. of Cell Biology, Cleveland Clinic Research Institute, Cleveland, OH 44195.
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↵‖ To whom correspondence should be addressed: ONYX Pharmaceuticals, 3031 Research Dr., Richmond, CA 94806. Tel.: 510-262-8735; Fax: 510-222-9758; E-mail: msymons{at}onyx-pharm.com.
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↵1 The abbreviations used are: PDGF, platelet-derived growth factor; LPA, lysophosphatidic acid; N17-Rac1, Asn-17 Rac1; ERK, extracellular signal-regulated kinase; A218/A222-MEK1, Ala-218/Ala-222-mitogen-activated protein kinase kinase.
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- Received June 25, 1997.
- Revision received September 25, 1997.
