Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex.

Abstract

Genetic studies have shown that the tuberous sclerosis complex (TSC) 1-TSC2-mammalian target of Rapamycin (mTOR) and the Hippo-Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1-TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.

• Authors: Ning Liang, Chi Zhang, Patricia Dill, Ganna Panasyuk, Delphine Pion, Vonda Koka, Morgan Gallazzini, Eric N Olson, Hilaire Lam, Elizabeth P Henske, Zheng Dong, Udayan Apte, Nicolas Pallet, Randy L Johnson, Fabiola Terzi, David J Kwiatkowski, Jean-Yves Scoazec, Guido Martignoni, Mario Pende
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 211 Issue 11 Pg. 2249-63 (Oct 20 2014) ISSN: 1540-9538 [Electronic] United States
• PMID: 25288394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Liang et al.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• Phosphoproteins
• Porphyrins
• TSC1 protein, human
• Tsc1 protein, mouse
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Verteporfin
• TOR Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Angiomyolipoma (genetics, metabolism)
• Animals
• Apoptosis (drug effects, genetics)
• Autophagy (drug effects, genetics)
• Cell Cycle Proteins
• Cell Proliferation
• Cell Survival (drug effects, genetics)
• Disease Models, Animal
• Gene Expression Regulation
• Humans
• Immunohistochemistry
• Kidney (metabolism, pathology)
• Mice
• Mice, Knockout
• Phosphoproteins (genetics, metabolism)
• Porphyrins (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis (genetics, metabolism, pathology)
• Tuberous Sclerosis Complex 1 Protein
• Tumor Suppressor Proteins (genetics, metabolism)
• Up-Regulation
• Verteporfin
• YAP-Signaling Proteins