The Fat1 Cadherin Integrates Vascular Smooth Muscle Cell Growth and Migration Signals

The significance of cadherin superfamily proteins in vascular smooth muscle cell (VSMC) biology is undefined. Here we describe recent studies of the Fatl protocadherin. Fatl expression in VSMCs increases significantly after arterial injury or growth factor stimulation. Fat1 knockdown decreases VSMC migration in vitro, but surprisingly, enhances cyclin D1 expression and proliferation. Despite limited similarity to classical cadherins, the Fat1 intracellular domain ($Fat1_{IC}$) interacts with$\beta-catenin$, inhibiting both its nuclear localization and transcriptional activity. Fatl undergoes cleavage and$Fat1_{IC}$species localize to the nucleus; however, inhibition of the cyclin D1 promoter by truncated$Fatl_{IC}$proteins corresponds to their presence outside the nucleus, which argues against repression of$\beta-catenin-dependent$transcription by nuclear$Fat1_{IC}$. These findings extend recent observations about Fat1 and migration in other cell types, and demonstrate for the first time its anti-proliferative activity and interaction with$\beta-catenin$. Because it is induced after arterial injury, Fat1 may control VSMC functions central to vascular remodeling by facilitating migration and limiting proliferation.