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Philip Stork earned his M.D. at Columbia University in 1984 and went on to a residency in Pathology at Harvard Medical School and a fellowship at Tufts-New England Medical Center. He became an assistant professor in the Department of Pathology at Tufts in 1988. Stork was appointed as an assistant scientist at the Vollum Institute in 1990 and was promoted to scientist in 1997, and Senior Scientist in 2005. He holds joint appointments in the Department of Pathology and the Department of Cell and Developmental Biology in the School of Medicine. He did his undergraduate work at Harvard University and earned an M.S. from Stanford University. Research InterestsPhilip Stork and his colleagues use molecular and biochemical approaches to understand how hormones and growth factors convey signals from the outside of a cell to the nucleus to induce cellular responses. Over the past few years, the Stork laboratory has tried to understand a fundamental question in the field of signal transduction: how can qualitative changes in the magnitude and duration of a single signaling cascade lead to qualitative changes in the cellular response? Two fundamental cellular responses are proliferation and differentiation. Researchers in the laboratory have been studying this question using a signaling molecule called mitogen-activated protein kinase (MAP kinase) or ERK (extracellular signal-related kinase) as a model system to examine signals governing proliferation and differentiation. The Stork laboratory has recently discovered a novel pathway for MAP kinase activation. The components of this novel pathway are the small G protein Rap1 and the protein kinase B-Raf. The laboratory has identified this pathway as a critical regulator of MAP kinase signaling in neuronal differentiation, gene expression, and cell growth. Current efforts are directed toward determining the requirement of this novel signaling cascade in developmental paradigms and pathophysiological models of disease. The ability of Rap1 to augment signaling via B-Raf and ERKs is cell-type specific, largely due to the cell-type specific expression of B-Raf. Current efforts are underway to determine the extent and role of B-Raf expression in the developing embryo and the adult. In cells that lack B-Raf, the role of Rap1 is less clear. The laboratory is currently using transgenic model systems to examine Rap1’s function in B-Raf-negative cells within the immune system. Rap1 is highly related to the small G protein Ras. The ability of the cell to respond to multiple extracellular signals by activating Ras and Rap1 is achieved by a large family of guanine nucleotide exchanger proteins that activate either Ras or Rap1. The laboratory is currently examining the function of these exchangers in dictating the cellular response to extracellular signals. The focus of these studies is to determine whether distinct guanine nucleotide exchange proteins activate distinct pools of Rap1 that couple to selective downstream targets. It is hoped that these studies will help explain how Rap1 integrates diverse signaling pathways in mammalian cells. Selected PublicationsObara, Y., Labudda, K., Dillon,T.J., and Stork, P. J.S. (2004) PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells. J. Cell Science 117:6085-6094. Carey, K.D., Watson, D.E., Pessin, J.E., and Stork, P.J.S. (2003) The requirement of specific membrane domains for Raf-1 phosphorylation and activation. J. Biol. Chem. 278:3185-3196. Stork, P.J.S. (2003) Does Rap1 deserve a bad rap? Trends Biochem. Sci. 28:267-275. Dillon, T.J., Karpinsky, V., Wetzel, S.A., Parker, D.C., Shaw, A.S., and Stork, P.J.S. (2003) Ectopic B-Raf expression enhances extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen presenting cell-induced anergy. J. Biol. Chem. 278:35940-35949. Schmitt, J.M. and Stork, P.J.S. (2002) PKA phosphorylation of Src mediates cAMP's inhibition of cell growth via Rap1. Mol. Cell 9:85-94. York, R.D., Yao, H., Dillon, T., Ellig, C.L., Eckert, S.P., McCleskey E.W., and Stork, P.J.S. (1998) Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392:622-626.
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