von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germ 
line mutation of the von Hippel-Lindau tumor suppressor gene (VHL). Tumors 
observed in this disorder include retinal and central nervous system 
hemangioblastomas, clear cell renal carcinomas and pheochromocytomas. The VHL 
gene product, pVHL, is a component of a ubiquitin ligase which targets the 
transcription factor known as hypoxia-inducible factor (HIF) for degradation in 
the presence of oxygen. pVHL also plays roles in the control of extracellular 
matrix formation and cell-cycle exit. Different VHL mutations confer different 
site-specific risks of cancer. Type 2C VHL mutations confer an increased risk of 
pheochromocytoma without the other stigmata of VHL disease. Here we report that 
the products of such type 2C VHL alleles retain the ability to down regulate HIF 
but are defective for promotion of fibronectin matrix assembly. Furthermore, 
pVHL L188V, a well studied type 2C mutant, retained the ability to suppress 
renal carcinoma growth in vivo. These studies strengthen the notion that HIF 
deregulation plays a causal role in hemangioblastoma and renal carcinoma, and 
raises the possibility that abnormal fibronectin matrix assembly contributes to 
pheochromocytoma pathogenesis in the setting of VHL disease.