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LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function.
- Source :
-
Nature communications [Nat Commun] 2019 Dec 17; Vol. 10 (1), pp. 5755. Date of Electronic Publication: 2019 Dec 17. - Publication Year :
- 2019
-
Abstract
- Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.
- Subjects :
- Animals
Autophagy drug effects
Beclin-1 metabolism
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular immunology
Carcinoma, Hepatocellular mortality
Cell Line, Tumor
Cell Proliferation
Cell Survival drug effects
Datasets as Topic
Disease-Free Survival
Drug Resistance, Neoplasm immunology
Hippo Signaling Pathway
Humans
Kaplan-Meier Estimate
Liver pathology
Liver Neoplasms drug therapy
Liver Neoplasms immunology
Liver Neoplasms mortality
Lysine metabolism
Mice
Mice, Knockout
Organoids
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases immunology
Protein Stability
Signal Transduction drug effects
Signal Transduction immunology
Sorafenib pharmacology
Sorafenib therapeutic use
Tumor Suppressor Proteins immunology
Ubiquitination
Xenograft Model Antitumor Assays
Autophagy immunology
Carcinoma, Hepatocellular pathology
Cell Survival immunology
Liver Neoplasms pathology
Protein Serine-Threonine Kinases metabolism
Tumor Suppressor Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31848340
- Full Text :
- https://doi.org/10.1038/s41467-019-13591-7