Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer

Insulin-like growth factor-I (IGF-I)-mediated signaling is thought to be involved in the regulation of multiple cellular functions in different tumors including renal cell carcinoma (RCC). Blocking IGF-I signaling by any of the several strategies abolishes or delays the progression of a variety of tumors in animal models. Herein, we demonstrate that in RCC cell lines, IGF-I- mediated signaling is found to be inhibited in the presence of wild type yon Hippel-Lindau (VHL) tumor suppresser gene. Moreover, molecular modeling and biochemical approaches have revealed that β-domain of the VHL gene product by interacting directly with protein kinase Cδ inhibits its association with IGF-IR for downstream signaling. We also demonstrated that RCC has IGF-I- mediated invasive activity where protein kinase Cδ is an important downstream molecule, and this invasiveness can be blocked by wild type VEIL. These experiments thus elucidate a novel tumor suppresser function of VHL with its unique kinase inhibitory domain.