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J. Biol. Chem., Vol. 283, Issue 36, 24982-24990, September 5, 2008

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Inadequate Activation of the GTPase RhoA Contributes to the Lack of Fibronectin Matrix Assembly in von Hippel-Lindau Protein-defective Renal Cancer Cells^*

Monica Feijóo-Cuaresma¹, Fernando Méndez¹, Alfredo Maqueda, Miguel A. Esteban^¶, Salvador Naranjo-Suarez, Maria C. Castellanos, Mercedes Hernández del Cerro, Silvia N. Vazquez, Angeles García-Pardo, Manuel O. Landázuri², and Maria J. Calzada²³

From the Servicio de Inmunología, Hospital de la Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Diego de León 62, 28006 Madrid, Spain, the Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, CSIC, 28040 Madrid, Spain, and the ^¶Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China

The von Hippel-Lindau (VHL) tumor suppressor gene regulates extracellular matrix deposition. In VHL negative renal cancer cells, VHL(-), the lack of fibronectin matrix assembly is thought to promote and maintain tumor angiogenesis allowing vessels to infiltrate tumors. Therefore, and considering the importance of this process in tumor growth, we aimed to study why VHL(-) renal cancer cells fail to form a proper extracellular matrix. Our results showed that VHL(-) cells were not defective in fibronectin production and that the fibronectin produced by these cells was equally functional in promoting cell adhesion and matrix assembly as that produced by VHL(+) cells. We have previously reported that VHL(-) cells fail to form β1 integrin fibrillar adhesions and have a diminished organization of actin stress fibers; therefore, we aimed to study if the small GTPase family is involved in this process. We found that activation of the RhoA GTPase was defective in VHL(-) cells, and this was possibly mediated by an increased activation of its inhibitor, p190RhoGAP. Additionally, the expression of constitutively active RhoA in VHL(-) cells resulted in formation of a fibronectin matrix. These results strongly suggest an important role for RhoA in some of the defects observed in renal cancer cells.

Received for publication, November 15, 2007 , and in revised form, April 28, 2008.

^* This work was supported in part by SAF2006-04013 from the Ministerio de Educación y Ciencia (MEC) (to M. J. C.), SAF2007-60592 and RECAVA C03/01 (to M. O. L.), and PI060400 from the Ministerio de Sanidad y Consumo and the Fundacion de Investigacion Medica Mutua Madrileña (to A. G. -P.). 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 supplemental methods and Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² Both senior authors contributed equally to this work.

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³ To whom correspondence should be addressed: Hospital de la Princesa, Diego de Leon 62, 28006 Madrid, Spain. Tel.: 01134-91-5202371; Fax: 01134-91-5202374; E-mail: mcalzada.hlpr{at}salud.madrid.org.

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