Novel role of STRAP in progression and metastasis of colorectal cancer through Wnt/β-catenin signaling.

Serine-Threonine Kinase Receptor-Associated Protein (STRAP) interacts with a variety of proteins and influences a wide range of cellular processes. Aberrant activation of Wnt/beta-catenin signaling has been implicated in the development of colorectal cancer (CRC). Here, we show the molecular mechanism by which STRAP induces CRC metastasis by promoting beta-catenin signaling through its stabilization. We have genetically engineered a series of murine and human CRC and lung cancer cell lines to investigate the effects of STRAP on cell migration and invasion in vitro, and on tumorigenicity and metastasis in vivo. Downregulation of STRAP inhibits invasion, tumorigenicity, and metastasis of CRC cells. Mechanistically, STRAP binds with GSK-3 beta and reduces the phosphorylation, ubiquitylation, and degradation of beta-catenin through preventing its binding to the destruction complex. This leads to an inhibition of Wnt/beta-catenin signaling and reduction in the expression of downstream targets, such as Cyclin D1, matrix metalloproteinases 2 and 9, and beta-TrCP. In human CRC specimens, higher STRAP expression correlates significantly with beta-catenin expression with increased nuclear levels (R = 0.696, p < .0001, n = 128). Together, these results suggest that STRAP increases invasion and metastasis of CRC partly through inhibiting ubiquitin-dependent degradation of beta-catenin and promoting Wnt/beta-catenin signaling.