The Hippo-of Taz Signaling Pathway On The Regulation Of Cell Growth

The Hippo Pathway was first identified as a novel organ size control apparatus during Drosophila development by coordination cell proliferation and apoptosis. The core components function as a kinase cascade, phosphorylates Yorkie, down-regulates its transcription activation, and then define cell number and organ size. Dysfunction of Hippo pathway leads to organ hypertrophy and tissue cancerous growth. In mammalian cells, the components of Hippo pathway are highly conserved; most of them have been characterized as tumor suppressor genes which often found silencing or loss of function in human cancer tissue. TAZ is a transcription co-activator, one of Yorkie orthologs in mammalian cell. Our study has demonstrated that TAZ functions as the downstream factor of Hippo pathway. We found four conserved HXRXXS motif in TAZ; Lats2, a kinase homolog of Wts in Drosophila, phosphorylates the serine residue of the motif and creates a 14-3-3 binding sites, which results in TAZ cytoplasmic retention. Disruption the phosphorylation leads to constitutive activation of TAZ including nuclear import and transcription activation, consequently stimulates cell proliferation, induces EMT (Epithelial-Mesenchymal Transition) and promotes cell migration. We also defined TEAD, a family of transcription factor, mediates TAZ function in promoting cell proliferation and inducing EMT. We found the key residue for TAZ-TEAD binding, S51A mutation or TEAD silencing leads to the block of TAZ tumorigenetic function in stimulating cell proliferation, inducing EMT and promoting cell migration. Our work established the connection between TAZ and Hippo pathway. It is very meaningful to fully understand the physiological function of the pathway, and the role of TAZ/TEAD playing in tumorigenesis and human cancer development.