Itch E3 ubiquitin ligase regulates LATS1 tumour suppressor stability

• Main Author: Ho, King Ching
• Other Authors: Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))
• Language: en; en
• Published: 2011
• Subjects: Proteomics; Ubiquitination; Tumour suppressor; Protein stability
• Online Access: http://hdl.handle.net/1974/6424

The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in a broad spectrum of human cancers. It is a central player of the emerging Hippo-LATS tumour suppressor pathway, which plays important roles in cell proliferation, apoptosis, and stem cell differentiation. Despite the ample data supporting a role of LATS1 in tumour suppression, how LATS1 is regulated at the molecular level remains largely unknown. In this study, we have identified Itch, a HECT class E3 ubiquitin ligase, as a novel binding partner of LATS1. Itch can complex with LATS1 both in vitro and in vivo through the PPxY motifs of LATS1 and the WW domains of Itch. Significantly, we found that over-expression of Itch promoted LATS1 degradation by polyubiquitination through the 26S proteasome pathway. On the other hand, knockdown of endogenous Itch by shRNAs provoked stabilization of endogenous LATS1 proteins. Finally, through several functional assays, we also revealed that change of Itch abundance alone is sufficient for altering LATS1-mediated downstream signaling, negative regulation of cell proliferation, and induction of apoptosis. Together, our study identifies E3 ubiquitin ligase Itch as the first negative regulator of LATS1 and presents for the first time a possibility of targeting LATS1/Itch interaction as a therapeutic strategy in cancer. === Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2011-04-26 22:25:46.008