Photo of Joseph Avruch,  MD

Joseph Avruch, MD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6909


avruch@molbio.mgh.harvard.edu

Joseph Avruch, MD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Chief, Diabetes Unit, Medicine, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Avruch, Joseph MD Cell Regulation by small GTPases and Protein kinases

Elucidation of the TOR pathway. TOR is a giant protein kinase that responds to nutrient sufficiency and insulin/IGF-1 (and other mitogens) to control the growth/size of all cells (e.g., pancreatic beta cells), and the proliferation of some, such as T cells and vascular smooth muscle cells. TOR also negatively regulates insulin signaling to PI-3 kinase. TOR functions in two physically separate, independently regulated hetero-oligomeric complexes (mTOR complexes 1 and 2); The major effort is directed at understanding how the small, ras-like GTPase, Rheb, which we showed acts directly on the mTOR polypeptide, controls the kinase activity of mTORC1. The activity of mTORC1 is also controlled by amino acids especially leucine. We showed that leucine controls the interaction of Rheb with mTOR in vivo; the basis for this control appears to be mediated by another set of small GTPases, the Rag polypeptides, and current effort is focused on the regulation of the latter. mTOR interaction with its substrates (e.g., 4E-BP, S6K1) appears to be regulated; the basis for this regulation is under study. Finally, the mechanisms by which mTOR gates the translation of the IGF2 mRNA isoform specifically associated with the RNA binding protein IMP2, as well as the identification of the cohort of mRNAs bound to IMP2 is under investigation; IMP2 is a candidate T2DM locus and fetal IGF2 is relevant to the nutrient control of fetal growth.

The regulation and physiologic functions of the Mst1 and Mst2 protein kinases, which are the mammalian orthologs of the “hippo” kinase, a central element in an anti-proliferative developmental pathway defined in Drosophila. We identified Mst1/2 as constitutive partners of the tumor suppressor proteins RASSF1/Nore1; the latter bind specifically to the active forms of the Ras and Rap1 small GTPases. Transfection and biochemical analyses defined the regulation of the Nore1/Mst1 complex by ras-like GTPases and identified the cyclin-like polypeptide Mob1 as a preferred Mst1/2 substrate. To gain an understanding of the physiologic functions of these kinases, Mst1 and Mst2 KO mice were generated. The Mst1 KO mice exhibit major abnormalities in the function of T cells; elimination of Mst1 greatly enhances the proliferative response of mature, naïve T cells to stimulation of the T cell antigen receptor, whereas the clustering and activation of integrins is severely impaired. Surprisingly, these effects of Mst1 KO are independent of the downstream elements of the canonical “hippo” pathway. In contrast, Mst1 and Mst2 act as redundant tumor suppressors in liver, largely through inhibition of the YAP transcriptional coactivator, paralleling the behavior of “hippo”. The regulation of Mst1/Mst2 in their multiple signaling pathways and their physiologic targets are under investigation.

 

Publications

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  • Fitamant J, Kottakis F, Benhamouche S, Tian HS, Chuvin N, Parachoniak CA, Nagle JM, Perera RM, Lapouge M, Deshpande V, Zhu AX, Lai A, Min B, Hoshida Y, Avruch J, Sia D, Campreciós G, McClatchey AI, Llovet JM, Morrissey D, Raj L, Bardeesy N. YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Rep 2015. PubMed
  • Papageorgiou A, Rapley J, Mesirov JP, Tamayo P, Avruch J. A Genome-Wide siRNA Screen in Mammalian Cells for Regulators of S6 Phosphorylation. PLoS ONE 2015; 10:e0116096. PubMed
  • Oshiro N, Rapley J, Avruch J. Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging. J Biol Chem 2014; 289:2658-74. PubMed
  • Wu H, Xiao Y, Zhang S, Ji S, Wei L, Fan F, Geng J, Tian J, Sun X, Qin F, Jin C, Lin J, Yin ZY, Zhang T, Luo L, Li Y, Song S, Lin SC, Deng X, Camargo F, Avruch J, Chen L, Zhou D. The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense. Cell Rep 2013; 3:1663-77. PubMed
  • Gao T, Zhou D, Yang C, Singh T, Penzo-Méndez A, Maddipati R, Tzatsos A, Bardeesy N, Avruch J, Stanger BZ. Hippo Signaling Regulates Differentiation and Maintenance in the Exocrine Pancreas. Gastroenterology 2013. PubMed
  • Avruch J, Zhou D, Fitamant J, Bardeesy N, Mou F, Barrufet LR. Protein kinases of the Hippo pathway: Regulation and substrates. Semin Cell Dev Biol 2012; 23:770-84. PubMed
  • Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD. Yap1 Acts Downstream of 留-Catenin to Control Epidermal Proliferation. Cell 2011; 144:782-95. PubMed
  • Park J, Kang SI, Lee SY, Zhang XF, Kim MS, Beers LF, Lim DS, Avruch J, Kim HS, Lee SB. Tumor suppressor Ras-association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis. J Biol Chem 2010; 285:35029-38. PubMed
  • Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, Lauwers GY, Thasler W, Lee JT, Avruch J, Bardeesy N. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 2009; 16:425-38. PubMed
  • Avruch J, Xavier R, Bardeesy N, Zhang XF, Praskova M, Zhou D, Xia F. Rassf family of tumor suppressor polypeptides. J Biol Chem 2009; 284:11001-5. PubMed
  • Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 2009; 296:E592-602. PubMed
  • Avruch J, Long X, Lin Y, Ortiz-Vega S, Rapley J, Papageorgiou A, Oshiro N, Kikkawa U. Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. Biochem Soc Trans 2009; 37:223-6. PubMed
  • Patursky-Polischuk I, Stolovich-Rain M, Hausner-Hanochi M, Kasir J, Cybulski N, Avruch J, Rüegg MA, Hall MN, Meyuhas O. The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner. Mol Cell Biol 2009; 29:640-9. PubMed
  • Zhou D,Medoff BD,Chen L,Li L,Zhang XF,Praskova M,Liu M,Landry A,Blumberg RS,Boussiotis VA,Xavier R,Avruch J. The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells. Proc Natl Acad Sci U S A 2008; 105:20321-6. PubMed
  • Rapley J, Nicolàs M, Groen A, Regué L, Bertran MT, Caelles C, Avruch J, Roig J. The NIMA-family kinase Nek6 phosphorylates the kinesin Eg5 at a novel site necessary for mitotic spindle formation. J Cell Sci 2008; 121:3912-21. PubMed
  • Anguera MC,Liu M,Avruch J,Lee JT. Characterization of two Mst1-deficient mouse models. Dev Dyn 2008; 237:3424-34. PubMed
  • Hagan GN, Lin Y, Magnuson MA, Avruch J, Czech MP. A Rictor-Myo1c complex participates in dynamic cortical actin events in 3T3-L1 adipocytes. Mol Cell Biol 2008; 28:4215-26. PubMed
  • Praskova M, Xia F, Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol 2008; 18:311-21. PubMed
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