SRC activates TAZ for intestinal tumorigenesis and regeneration. (1st December 2017) - Byun, Mi Ran
Abstract: Proto-oncogene tyrosine-protein kinase Src (cSRC) is involved in colorectal cancer (CRC) development and damage-induced intestinal regeneration, although the cellular mechanisms involved are poorly understood. Here, we report that transcriptional coactivator with PDZ binding domain (TAZ) is activated by cSRC, regulating CRC cell proliferation and tumor formation, where cSRC overexpression increases TAZ expression in CRC cells. In contrast, knockdown of cSRC decreases TAZ expression. Additionally, direct phosphorylation of TAZ at Tyr316 by cSRC stimulates nuclear localization and facilitates transcriptional enhancer factor TEF-3 (TEAD4)-mediated transcription. However, a TAZ phosphorylation mutant significantly decreased cell proliferation, wound healing, colony forming, and tumor formation. In a CRC mouse model, Apc Min/+, activated SRC expression was associated with increased TAZ expression in polyps and TAZ depletion decreased polyp formation. Moreover, intestinal TAZ knockout mice had intestinal regeneration defects following γ-irradiation. Finally, significant correspondence between SRC activation and TAZ overexpression was observed in CRC patients. These results suggest that TAZ is a critical factor for SRC-mediated intestinal tumor formation and regeneration. Highlights: TAZ is activated by cSRC in colorectal cell proliferation and tumor formation. cSRC phosphorylates TAZ at Tyr316 and stimulates nuclear localization of TAZ and facilitates TEAD4-mediated transcription. In Apc Min/+ mouse, TAZ depletion decreases polyp formation. Intestinal specific TAZ knockout mice have intestinal regeneration defects following γ-irradiation. Correspondence between SRC activation and TAZ overexpression is observed in CRC patients.