Inadequate activation of the GTPase RhoA contributes to the lack of fibronectin matrix assembly in von Hippel-Lindau protein-defective renal cancer cells.
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 beta1 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.
Servicio de Inmunología, Hospital de la Princesa, Departamento de Medicina, Universidad Autónoma de Madrid, Diego de León 62, 28006 Madrid, Spain.
Monica
M
Feijóo-Cuaresma
Fernando
F
Méndez
Alfredo
A
Maqueda
Miguel A
MA
Esteban
Salvador
S
Naranjo-Suarez
Maria C
MC
Castellanos
Mercedes Hernández
MH
del Cerro
Silvia N
SN
Vazquez
Angeles
A
García-Pardo
Manuel O
MO
Landázuri
Maria J
MJ
Calzada
D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C513043:ARHGAP5 protein, human; D005353:Fibronectins; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; C066737:RHOA protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D020742:rhoA GTP-Binding Protein; C497446:VHL protein, human