WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells

The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in various human cancers. LATS1 has recently been identified as a central player of the emerging Hippo signaling pathway, which plays important roles in organ size control, tumorigenesis, and...

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Bibliographic Details
Published in:PloS one 2013-04, Vol.8 (4), p.e61027-e61027
Main Authors: Yeung, Benjamin, Ho, King-Ching, Yang, Xiaolong
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biology
Breast cancer
Breast Neoplasms
Cancer
Cancer cells
Cancer therapies
Cell differentiation
Cell growth
Cell Proliferation
Cercopithecus aethiops
COS Cells
Degradation
Drosophila
Drug delivery
Drugs
Enzyme Stability
Female
Gene amplification
Gene expression
Health aspects
HEK293 Cells
Humans
Insects
Kinases
MCF-7 Cells
Medical research
Medicine
Metastasis
Overexpression
Plasmids
Proteasome 26S
Proteasome Endopeptidase Complex - metabolism
Protein Binding
Protein Interaction Domains and Motifs
Protein Interaction Mapping
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - metabolism
Protein-serine/threonine kinase
Proteins
Proteolysis
Regulators
Ribonucleic acid
RNA
RNA-mediated interference
Senescence
Signal transduction
Signaling
Stability
Stem cells
Threonine
Tumor suppressor genes
Tumorigenesis
Ubiquitin
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary:The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in various human cancers. LATS1 has recently been identified as a central player of the emerging Hippo signaling pathway, which plays important roles in organ size control, tumorigenesis, and stem cell differentiation and renewal, etc. Although mounting evidence supports a role of LATS1 in tumor suppression and tumorigenesis, how LATS1 is regulated at the molecular level is not fully understood. Recently several positive regulators of LATS1 (Mst1/2, MOB1, Kibra, etc) have been identified but how LATS1 is negatively regulated is still largely unknown. We have recently identified Itch, a member of the NEDD4-like family E3 ubiquitin ligases, as a novel negative regulator of LATS1. However, whether other ubiquitin ligases modulate LATS1 stability and function is unclear. By screening many E3 ligases of the NEDD4-like family using over-expression and short-interference RNA knockdown approaches, we have identified WWP1 E3 ligase as another novel negative regulator of LATS1. We have provided in vitro and in vivo evidence that WWP1 is essential for LATS1 stability and negatively regulate LATS1 by promoting LATS1 degradation through polyubiquitination and the 26S proteasome pathway. Importantly, we also showed that degradation of LATS1 is critical in mediating WWP1-induced increased cell proliferation in breast cancer cells. Since WWP1 is an oncogene and LATS1 is a tumor suppressor gene in breast cancer, our studies provide a promising therapeutic strategy in which developed drugs targeting WWP1 cause activation of LATS1 in suppressing breast cancer cell growth.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0061027