[beta]-catenin is a multifunctional protein serving both as a structural element in cell-adhesion and as a signaling component in the Wnt pathway, regulating embryogenesis and tumorigenesis. The signaling fraction of [beta]-catenin is tightly controlled by the APC-Axin-GSK3[beta] complex, which targets it for proteasomal degradation. It has been recently shown that Ca2+ release from internal stores results in nuclear export and calpain-mediated degradation of [beta]-catenin in the cytoplasm. Here we have highlighted the critical relevance of constitutive calpain pathway in the control of [beta]-catenin levels and functions showing that siRNA-knockdown of endogenous calpain per se (i.e. in the absence of external stimuli) induces increase in the free-transcriptional competent pool of endogenous [beta]-catenin. We further characterized the role of the known calpain inhibitors, Gas2 and Calpastatin, demonstrating that they can also control levels, function and localization of [beta]-catenin through endogenous calpain regulation. Finally we present Gas2DN as a new tool for regulating calpain activity, providing evidence that it counteracts the described effects of both Gas2 and Calpastatin on [beta]-catenin, and that it works via calpain independently of the classical GSK3[beta]- and proteasome-pathway. Moreover we provide in vitro biochemical evidence showing that Gas2DN can increase the activity of calpain and that in vivo it can induce degradation of stabilized/mutated [beta]-catenin. In fact in a context where the classical proteasome pathway is impaired, as in colon cancer cells, Gas2DN biological effects accounted for a significant reduction in proliferation and anchorage-independent growth of colon cancer.