Joseph Avruch MD PhD
Dr. Avruch is a Professor of Medicine at the Harvard Medical School in the Department of Molecular Biology, and has been Chief of the Diabetes Unit in the department of Medicine at the MGH since 1979. He is director of the NIH sponsored Boston Area Diabetes and Endocrinology Research Center, and a member of the Board of Scientific Councilors of the National Institute of Diabetes, Digestive and Kidney Diseases.
Dr. Avruch directs a vigorous ongoing program of laboratory-based research, and is internationally recognized for a series of discoveries that have enabled an understanding of how insulin, related growth factors, as well as insulin antagonists control cell function. He remains active in clinical care and teaching.
Cell Regulation by small GTPases and Protein Kinases
The research program is aimed at identifying the molecular structure, function and regulation of the elements that mediate signal transduction initiated by the insulin receptor, related receptor tyrosine kinases and counter-acting, anti-insulin signalling pathways. As elucidation of the signalling pathways responsive to insulin progressed, it became evident that many of the effectors identified also participated in the implementation of mitogenic and cell differentiation programs. Thus the mechanisms uncovered in this effort proved to have important implications not only for metabolic regulation and its disorders i.e., diabetes and obesity, but also for states characterized by disordered cell growth regulation.
1) Elucidation of the Insulin and Nutrient regulation of protein synthesis: A long-term interest derives from the early discovery that activated Ser-Thr specific protein kinases play a central role in insulin and growth factor signal transduction. Although many insulin-regulated kinases are now known, one of the first identified was the p70S6kinase. This is now known to be a key regulator of the facultative component of protein synthesis responsible for cell growth in response to anabolic and mitogenic stimuli. Two convergent signal transduction pathways control the activation of this kinase: one flows through the PI-3 kinase, and the protein kinase PDK1, through PKB to the Tuberous Sclerosis complex and small GTPase, Rheb, to control the giant checkpoint protein kinase mTOR, the target of the immunosuppressive drug, rapamycin. Energy sufficiency, acting through the AMP-activated protein kinase also regulates this pathway at the level of TSC2. The second pathway is regulated by the sufficiency of intracellular amino acids (primarily leucine) through unknown elements to control mTOR signalling. Tor functions in a complex with several other proteins and the regulation of this complex is the focus of current work.
2) A Ras regulated tumor suppressor pathway: Work in this lab during the 1990’s identified the interaction of the Ras oncogene with its primary target, the Raf kinase, and elucidated the mechanism of activation of Raf. Parallel efforts identified NORE1, a novel noncatalytic polypeptide that bound specifically to Ras-GTP in a manner analogous to Raf, and therefore is a likely Ras effector. NORE is tumor suppressor and a negative regulator of cell proliferation, homologous to the tumor suppressor RASSFIA; the gene encoding RASSF1A is located on Chr3p21, and exhibits LOH in most lung and many other cancers. NORE and RASSF1A both bind to the proapoptotic protein kinase, MST, and the complex of NORE and MST appears to mediate the apoptosis induced by overexpression of activated mutants of Ki-Ras. The roles of these elements in normal cell physiology and in carcinogenesis is under investigation.
3) The regulation and roles of several members of the NIMA-related protein kinases: Eleven members of this protein kinase subfamily exist in man; we have characterized Nek6 and 7 and their immediate upstream activator, Nercc1/Nek9 as well as Nek1. The Nercc1 kinase is activated in mitosis, and interference with Nercc1, both in mammalian cells and Xenopus oocyte extracts, results in disorganization of the mitotic spindle leading to prometaphase arrest or aberrant chromosomal segregation. Nercc1 binds the Ran GTPase and is avidly phosphorylated by cdc2, and in turn phosphorylates and activates Nek6 and 7 protein kinases. The regulation of Nercc1, and the targets of Nercc1 and Nek6/7 are under investigation. Nek1 mutation in the mouse results in polycystic kidney disease and male sterility. In cell culture, Nek1 is activated in mitosis and is intimately associated with microtubular structures, including the mitotic spindle and the nonmotile cilia of renal epithelia.