The PtdIns3-phosphatase MTMR3 Interacts with MTORC1 and Suppresses Its Activity

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 2016 Jan 21

PMID 26787466

Citations 17

Authors

Feike Hao

Takashi Itoh

Eiji Morita

Kanae Shirahama-Noda

Tamotsu Yoshimori

Takeshi Noda

Affiliations

Soon will be listed here.

Abstract

Macroautophagy is a major intracellular degradation system. We previously reported that overexpression of phosphatase-deficient MTMR3, a member of the myotubularin phosphatidylinositol (PI) 3-phosphatase family, leads to induction of autophagy. In this study, we found that MTMR3 interacted with mTORC1, an evolutionarily conserved serine/threonine kinase complex, which regulates cell growth and autophagy in response to environmental stimuli. Furthermore, overexpression of MTMR3 inhibited mTORC1 activity. The N-terminal half of MTMR3, including the PH-G and phosphatase domains, was necessary and sufficient for these effects. Phosphatase-deficient MTMR3 provided more robust suppression of mTORC1 activity than wild-type MTMR3. Furthermore, phosphatase-deficient full length MTMR3 and the phosphatase domain alone were localized to the Golgi. These results suggest a new regulatory mechanism of mTORC1 in association with PI3P.

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References

Potter C, Pedraza L, Xu T . Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol. 2002; 4(9):658-65. DOI: 10.1038/ncb840. View

Taguchi-Atarashi N, Hamasaki M, Matsunaga K, Omori H, Ktistakis N, Yoshimori T . Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. Traffic. 2010; 11(4):468-78. DOI: 10.1111/j.1600-0854.2010.01034.x. View

Nobukuni T, Kozma S, Thomas G . hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol. 2007; 19(2):135-41. DOI: 10.1016/j.ceb.2007.02.019. View

Clague M, Lorenzo O . The myotubularin family of lipid phosphatases. Traffic. 2005; 6(12):1063-9. DOI: 10.1111/j.1600-0854.2005.00338.x. View

Lorenzo O, Urbe S, Clague M . Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosome related functions. J Cell Sci. 2006; 119(Pt 14):2953-9. DOI: 10.1242/jcs.03040. View

Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis N, Izumi T . Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol. 2010; 190(4):511-21. PMC: 2928018. DOI: 10.1083/jcb.200911141. View

Benjamin D, Hall M . mTORC1: turning off is just as important as turning on. Cell. 2014; 156(4):627-8. DOI: 10.1016/j.cell.2014.01.057. View

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View

Thomas J, Zhang Y, Wei Y, Cho J, Morris L, Wang H . Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell. 2014; 26(5):754-69. PMC: 4288827. DOI: 10.1016/j.ccell.2014.09.008. View

10.

Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y . Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009; 20(7):1981-91. PMC: 2663915. DOI: 10.1091/mbc.e08-12-1248. View

11.

Betz C, Stracka D, Prescianotto-Baschong C, Frieden M, Demaurex N, Hall M . Feature Article: mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology. Proc Natl Acad Sci U S A. 2013; 110(31):12526-34. PMC: 3732980. DOI: 10.1073/pnas.1302455110. View

12.

Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N . Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009; 11(4):385-96. DOI: 10.1038/ncb1846. View

13.

Karanasios E, Stapleton E, Manifava M, Kaizuka T, Mizushima N, Walker S . Dynamic association of the ULK1 complex with omegasomes during autophagy induction. J Cell Sci. 2013; 126(Pt 22):5224-38. DOI: 10.1242/jcs.132415. View

14.

Ma X, Blenis J . Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009; 10(5):307-18. DOI: 10.1038/nrm2672. View

15.

Betz C, Hall M . Where is mTOR and what is it doing there?. J Cell Biol. 2014; 203(4):563-74. PMC: 3840941. DOI: 10.1083/jcb.201306041. View

16.

Mei J, Li Z, Gui J . Cooperation of Mtmr8 with PI3K regulates actin filament modeling and muscle development in zebrafish. PLoS One. 2009; 4(3):e4979. PMC: 2656612. DOI: 10.1371/journal.pone.0004979. View

17.

Schalm S, Blenis J . Identification of a conserved motif required for mTOR signaling. Curr Biol. 2002; 12(8):632-9. DOI: 10.1016/s0960-9822(02)00762-5. View

18.

Jewell J, Kim Y, Russell R, Yu F, Park H, Plouffe S . Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science. 2015; 347(6218):194-8. PMC: 4384888. DOI: 10.1126/science.1259472. View

19.

Noda T, Matsunaga K, Taguchi-Atarashi N, Yoshimori T . Regulation of membrane biogenesis in autophagy via PI3P dynamics. Semin Cell Dev Biol. 2010; 21(7):671-6. DOI: 10.1016/j.semcdb.2010.04.002. View

20.

Lorenzo O, Urbe S, Clague M . Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3. J Cell Sci. 2005; 118(Pt 9):2005-12. DOI: 10.1242/jcs.02325. View