Itch E3 ubiquitin ligase regulates LATS1 tumour suppressor stability
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 d...
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| Language: | en en |
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2011
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| Online Access: | http://hdl.handle.net/1974/6424 |
| Summary: | 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 |
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