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Activation of Small GTPase Rho Is Required for Autocrine Motility Factor Signaling¹

Metastasis Research Program, Karmanos Cancer Institute and the Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201 [S. T., S. K. G., V. H., A. R.], and Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, the Netherlands [J. G. C.]

The hallmark of tumor metastasis is the dissemination of cells from the primary growth site todistant organs. Autocrine motility factor (AMF), a tumor-associated C-X-X-C cytokine, the ligand for a unique 78 kDa seven transmembrane receptor, is a potent simulator of cell motility, a process that is a prerequisite for tumor progression and metastasis. Because little is known about AMF-dependent signaling, we sought to study whether AMF signaling involves family members of the Rho-like GTPases. AMF stimulation of human melanoma cells resulted in stress-fiber formation, concomitant with up-regulation and activation of both RhoA and Rac1 expression with no apparent changes in the expression level or activation state of Cdc42. Treatment of the cells with C3 exoenzyme before AMF stimulation inhibited both the formation of stress-fiber-like structures and the activation of RhoA. In addition, both c-Jun NH₂-terminal kinase 1 and c-Jun NH₂-terminal kinase 2 were simultaneously activated by AMF, supporting the notion that they are involved in the signaling pathway of RhoA. We thus conclude that AMF signaling shares a similar pathway to previously established paracrine factors signaling involving cytoskeletal rearrangement and morphological alterations mediated by the small RhoA-like GTPases.

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