Abstract von Hippel-Lindau (VHL) disease is a cancer syndrome, which includes renal cell carcinoma (RCC), and is caused by VHL mutations. Most, but not all VHL phenotypes are due to failure of mutant VHL to regulate constitutive proteolysis of hypoxia inducible factors (HIFs). Janus kinases (JAK1, 2, 3 and TYK2) promote cell survival and proliferation, processes tightly controlled by SOCS proteins, which have sequence and structural homology to VHL. We hypothesized that in VHL disease, RCC pathogenesis results from enhanced SOCS1 degradation, leading to upregulated JAK activity. We find that baseline JAK2, JAK3 and TYK2 activities are increased in RCC cell lines, even after serum deprivation or co-incubation with cytokine inhibitors. Furthermore, JAK activity is sustained in RCC stably expressing HIF2 shRNA. Invasion through Matrigel and migration in wound healing assays, in vitro correlates of metastasis, are significantly greater in VHL mutant RCC compared to wild-type cells, and blocked by dominant negative JAK expression or JAK inhibitors. Finally we observe enhanced SOCS2/SOCS1 co-precipitation and reduced SOCS1 expression due to proteasomal degradation in VHL-null RCC compared to wild-type cells. The data support a new HIF-independent mechanism of RCC metastasis, whereby SOCS2 recruits SOCS1 for ubiquitination and proteasome degradation, which leads to unrestricted JAK-dependent RCC invasion. In addition to commonly proposed RCC treatment strategies that target HIFs, our data suggest that JAK inhibition represents an alternative therapeutic approach.