Aberrant activation of the GTPase Ras – which regulates cell proliferation – is a major cause of human cancer, so diverse signalling mechanisms exist to regulate its activity. For instance, Kang-Yell Choi and colleagues previously showed that Wnt/β-catenin signalling regulates the degradation of the H-Ras isoform; now, they report on the underlying mechanism of this process (). The authors show that, in HEK293 cells, endogenous and overexpressed H-Ras are polyubiquitylated and degraded by the proteasome. Moreover, these processes are mediated by β-transducin-repeat-containing protein (β-TrCP) – a key subunit of the SCF E3 ubiquitin-ligase complex. Next, the authors show that Axin and APC, which are negative regulators of the Wnt/β-catenin pathway, destabilise H-Ras by enhancing its interaction with β-TrCP; by contrast, binding of β-TrCP to H-Ras, and polyubiquitylation of H-Ras, are both reduced in cells treated with Wnt3a. In colorectal cancer cells, H-Ras-dependent proliferation is reduced by β-TrCP. Importantly, mice treated intravenously with Wnt3a have higher levels of Ras and β-catenin than untreated controls. Together, these data indicate a novel mechanism for the regulation of H-Ras stability. Ras destabilisation by Wnt/β-catenin signalling might, the authors propose, act as a safeguard against tumourigenesis.
