Signal transduction pathways controlling growth and metabolism
The Avruch laboratory studies mammalian signal transduction pathways. Over time, the laboratory has described the composition, architecture and regulation of signal transduction pathways operating downstream of the insulin receptor and other receptor tyrosine kinases (S6 kinases, Raf, Ras, Rheb), inflammatory cytokines (Map3ks, Map2ks and Mapks of the SAPKs/Jnk pathway), nutrients (mTOR complex1, Rag GTPases), cell-cell contact (Mst1/Mst2 operating in the mammalian Hippo pathway) and cdk1/Plk1 in control of mitotic progression (the Nek9-Nek6/7 kinase cascade). At present, three projects are ongoing:
- Identification of the mechanisms through which amino acids enable mTOR complex 1 signaling. We described this regulation in 1998, and showed in 2005 that it results in part from the ability of amino acids to promote the interaction of mTOR with its immediate activator, Rheb. In 2008 others showed that this interaction requires the Rag GTPases. Recently, we and others have shown that the binding of mTORC1 to Rag although necessary, is not sufficient for mTORC1 activation. We now seek to identify the other components necessary for amino acid action and their mechanism of action.
- We identified the IGF2 mRNA binding proteins IMP1-3, as substrates of mTOR. Each IMP is cotranslationally phosphorylated by mTOR complex 2, a modification that in the case of IMP1, is necessary for proper splicing and translation of the IGF2 mRNA. In addition, IMP2 is post-translationally regulated by mTORC1. All three IMPs are expressed coordinately during mid-gestation in the mouse; IMP1 and IMP3 expression is largely extinguished before birth, whereas IMP2 continues to be widely expressed in adult life. IMP2 is of especial interest inasmuch as SNPs in the human IMP2 gene are associated with increased risk for T2DM. We have characterized mice lacking IMP2, which are lean, resistant to diet induced obesity, insulin sensitive and long-lived. We are investigating the molecular basis for these phenotypes in collaboration with D. Altshuler.
- The Mst1 and Mst2 protein kinases together serve as upstream elements in a tumor suppressor pathway that negatively regulates cell proliferation in liver and intestine by inhibition of the function of Yap and TAZ, oncogenic proliferative and anti-apoptotic transcriptional coregulators. Independently, Mst1 regulates T cell motility, proliferation and development into Treg by Yap/TAZ-independent pathways; we are seeking the identity of the effectors of Mst1 function in the lymphoid system in collaboration with R. Xavier.
1. Noriko Oshiro, Joseph Rapley, Joseph Avruch Amino Acids Activate Mammalian Target of Rapamycin (mTOR) Complex 1 without Changing Rag GTPase Guanyl Nucleotide Charging. J Biol Chem. 2014; 289(5): 2658–2674. PMCID: PMC3908400
2. Ning Dai, Joseph Rapley, Matthew Angel, M. Fatih Yanik, Michael D. Blower, Joseph Avruch mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev. 2011; 25(11): 1159–1172. PMCID: PMC3110954.
3. Ning Dai, Jan Christiansen, Finn C. Nielsen, Joseph Avruch. mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts Genes Dev. 2013; 27(3): 301–312. PMCID: PMC3576515
4. Dawang Zhou, Benjamin D. Medoff, Lanfen Chen, Lequn Li, Xian-feng Zhang, Maria Praskova, Matthew Liu, Aimee Landry, Richard S. Blumberg, Vassiliki A. Boussiotis, Ramnik Xavier, Joseph Avruch The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells. Proc Natl Acad Sci U S A. 2008; 105(51): 20321–20326. PMCID: PMC2600581.
5. Dawang Zhou, Claudius Conrad, Fan Xia, Ji-Sun Park, Bernhard Payer, Yi Yin, Gregory Y. Lauwers, Wolfgang Thasler, Jeannie T. Lee, Joseph Avruch, Nabeel Bardeesy. Mst1 and Mst2 maintain hepatocyte quiescence and suppress the development of hepatocellular carcinoma through inactivation of the Yap1 oncogene. Cancer Cell. 2009; 16(5): 425–438. PMCID: PMC3023165
6. Fan Mou, Maria Praskova, Fan Xia, Denille Van Buren, Hanno Hock, Joseph Avruch, Dawang Zhou. The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J Exp Med. 2012; 209(4): 741–759. PMCID: PMC3328371.