Philip Stork, M.D.
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, 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.
Summary of Current Research
Philip 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 discovered a novel pathway for MAP kinase activation involving the small G protein Rap1 and the protein kinase B-Raf. The laboratory has continued to study the function of 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.
One area of current interest is the notion of strength of MAP kinase signaling being able to dictate distinct responses. To this end the laboratory has examined mouse models that show intermediate level of signaling through the MAP kinase cascade. One target is the MAP kinase kinase kinase B-Raf. These studies have confirmed the idea that B-Raf expression is a developmental switch that selectively activates signals through the MAP kinase cascade. The laboratory is currently examining B-Raf’s role in T cell development using conditional ablation of B-Raf.
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. One area of interest is the model that subcellular localization of small G proteins dictates the choice of effectors. For Rap1, recruitment and activation of Rap1 at the plasma membrane is critical for its ability to activate ERKs. The recruitment can be at the level of the small G proteins or at the level of guanine nucleotide exchange proteins. We are currently examining the recruitment of EPAC2, a Rap1-specific exchanger to the plasma membrane. This recruitment is governed by Ras-dependent signals and provides a mechanism of crosstalk between Ras and Rap1. It is hoped that these studies will help explain how Rap1 integrates diverse signaling pathways in mammalian cells.
Li Y, Dillon TJ, Takahashi M, Earley KT, Stork PJS (2016). PKA-independent Ras activation cooperates with Rap1 to mediate activation of ERKs by cAMP. J. Biol. Chem. 291:21584-21595.
Takahashi M, Dillon TJ, Liu C, Kariya Y, Wang Z, Stork PJ. (2013) PKA-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. J. Biol. Chem. 288:27712-27723.
Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJ, Kornev AP, Taylor SS, Shaw AS. (2013) Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154:1036-1046.
Li Y, Takahashi M, Stork PJ. (2013) Ras-mutant cancer cells display B-Raf binding to Ras that activates extracellular signal-regulated kinase and is inhibited by protein kinase A phosphorylation. J. Biol. Chem. 288: 27646-27657.
Liu C, Takahashi M, Li Y, Dillon TJ, Kaech S, Stork PJ. (2010) The interaction of Epac1 and Ran promotes Rap1 activation at the nuclear envelope. Mol. Cell. Biol. 30:3956-3969.
Obara Y, Yamauchi A, Takehara S, Nemoto W, Takahashi M, Stork PJ, Nakahata N. (2009) ERK5 activity is required for nerve growth factor-induced neurite outgrowth and stabilization of tyrosine hydroxylase in PC12 cells. J. Biol. Chem. 284:23564-23573.
Liu C, Takahashi M, Li Y, Song S, Dillon TJ, Shinde U, Stork PJ. (2008) Ras is required for the cyclic AMP-dependent activation of Rap1 via Epac2. Mol. Cell Biol. 28:7109-7125.
Wang Z, Dillon TJ, Pokala V, Mishra S, Labudda K, Hunter B, Stork PJ. (2006) Rap1-mediated activation of extracellular signal-regulated kinases by cyclic AMP is dependent on the mode of Rap1 activation. Mol. Cell. Biol. 26:2130-2145.
Dillon TJ, Carey KD, Wetzel SA, Parker DC, Stork PJ. (2005) Regulation of the small GTPase Rap1 and ERKs by the costimulatory molecule CTLA-4. Mol. Cell. Biol. 25:4117-4128.
Stork PJ, Dillon TJ. (2005) Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions. Blood 106:2952-2961.
Stork PJ. (2003) Does Rap1 deserve a bad Rap? Trends Biochem. Sci. 28:267-275.
Schmitt JM, Stork PJ. (2002) PKA phosphorylation of Src mediates cAMP’s inhibition of cell growth via Rap1. Mol. Cell 9:85-94.
York RD, Yao H, Dillon T, Ellig CL, Eckert SP, McCleskey EW, Stork PJ. (1998) Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392:622-626.