LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Tang, Fengyuan and Gao, Ruize and Jeevan-Raj, Beena and Wyss, Christof B. and Kalathur, Ravi K. R. and Piscuoglio, Salvatore and Ng, Charlotte K. Y. and Hindupur, Sravanth K. and Nuciforo, Sandro and Dazert, Eva and Bock, Thomas and Song, Shuang and Buechel, David and Morini, Marco F. and Hergovich, Alexander and Matthias, Patrick and Lim, Dae-Sik and Terracciano, Luigi M. and Heim, Markus H. and Hall, Michael N. and Christofori, Gerhard. (2019) LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nature Communications, 10 (1). p. 5755.

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Research
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:06 Jan 2020 10:18
Deposited On:06 Jan 2020 10:18

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