Figure 1. Activation of the hepatocyte growth factor (HGF)/c-Met signaling pathway results in β-catenin tyrosyl phosphorylation, through interactions with the c-Met tyrosine kinase (TK) or with primary and/or secondary effectors. This results in the dissociation of β-catenin from E-cadherin in adherens junctions and its accumulation in the cytosol. If not rapidly ubiquitinated and degraded, cytosolic β-catenin translocates to the nucleus, where it regulates the transcription of genes that mediate processes that are known to contribute to tumorigenesis, malignancy, and metastasis. The product of the von Hippel-Lindau (VHL) tumor suppressor gene has been known to suppress RCC tumorigenesis through the ubiquitination and subsequent proteosomal destruction of hypoxia inducible factors (HIFs). As we recently reported, VHL protein is also critical for targeting cytoplasmic β-catenin for proteosomal destruction in renal epithelial cells; VHL gene loss in RCC thus promotes oncogenic signaling through both β-catenin and HIF pathways. ARNT, aryl hydrocarbon receptor nuclear translocator; TCF, T-cell factor; SH2, Src homology 2 domain.