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Activated G₁₃ Impairs Cell Invasiveness through p190RhoGAP-Mediated Inhibition of RhoA Activity

Department of Cellular and Molecular Physiopathology, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain

Requests for reprints: Joaquin Teixidó, Centro de Investigaciones Biológicas, Department of Cellular and Molecular Physiopathology, Ramiro de Maeztu 9, 28040 Madrid, Spain. Phone: 34-91-8373112; Fax: 34-91-5360432; E-mail: joaquint{at}cib.csic.es.

Key Words: Chemokines • Melanoma • Invasion • RhoGTPases • Metastasis

The GTPase RhoA is a downstream target of heterotrimeric G₁₃ proteins and plays key roles in cell migration and invasion. Here, we show that expression in human melanoma cells of a constitutively active, GTPase-deficient G₁₃ form (G₁₃QL) or lysophosphatidylcholine (LPC)-promoted signaling through G₁₃-coupled receptors led to a blockade of chemokine-stimulated RhoA activation and cell invasion that was rescued by active RhoA. Melanoma cells expressing G₁₃QL or cells stimulated with LPC displayed an increase in p190RhoGAP activation, and defects in RhoA activation and invasion were recovered by knocking down p190RhoGAP expression, thus identifying this GTPase-activating protein (GAP) protein as a downstream G₁₃ target that is responsible for these inhibitory responses. In addition, defective stress fiber assembly and reduced migration speed underlay inefficient invasion of G₁₃QL melanoma cells. Importantly, G₁₃QL expression in melanoma cells led to impairment in lung metastasis associated with prolonged survival in SCID mice. The data indicate that G₁₃-dependent downstream effects on RhoA activation and invasion tightly depend on cell type–specific GAP activities and that G₁₃-p190RhoGAP signaling might represent a potential target for intervention in melanoma metastasis. [Cancer Res 2008;68(20):8221–30]

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