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Role of the von Hippel-Lindau tumor suppressor gene in the formation of β1-integrin fibrillar adhesions

Abstract:

The von Hippel-Lindau tumor suppressor gene (VHL) is absent or inactivated in the VHL cancer syndrome and in most sporadic renal cancers. VHL is required for the assembly of a proper extracellular fibronectin matrix, although the exact mechanism remains unknown. In this report, we demonstrate that 786-O renal cancer cells are unable to organize an adequate matrix even in the presence of an excess of exogenous fibronectin. Because the formation of integrin fibrillar adhesions plays a pivotal role in the organization of extracellular fibronectin, we next examined the expression and subcellular distribution of integrins in VHL(-) cells and their wild-type VHL stably transfected counterparts. The levels of β1 and αv integrins were increased in VHL(-) cells when compared with VHL(+) transfectants. Early after plating, both VHL(+) and VHL(-) cells were capable of assembling classic "patch-like" αv focal contacts. As the culture advanced and cells became confluent, αv integrins partly relocated to the intercellular junctions in VHL(+) transfectants, which then developed large β1 fibrillar-type adhesions and anchored firmly to the substrate. In contrast, confluent VHL(-) cells were unable to assemble β1 fibrillar adhesions, and αv focal contacts remained unchanged at all stages of the culture. Exogenous activation of β1 integrins with either divalent cations or activating antibodies partly restored the capability of VHL(-) cells to assemble β1 fibrillar adhesions and fibronectin fibers. Finally, pulse-chase studies of metabolically labeled 786-O cells revealed that the maturation of the common β1-integrin chain was delayed in VHL(-) cells when compared with VHL(+) cells. Our results show that VHL is an important regulator of integrins and is essential for the formation of β1 fibrillar adhesions. These findings help to explain the abnormal extracellular matrix organization and increased motility of VHL(-) renal cancer cells.