Philip J. S. Stork, M.D.

Philip Stork, MD

Senior Scientist, Vollum Institute


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, Developmental & Cancer 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.

Koberstein JN, Stewart ML, Smith CB, Tarasov AI, Ashcroft FM, Stork PJS, Goodman RH. (2022) Monitoring glycolytic dynamics in single cells using a fluorescent biosensor for fructose 1,6-bisphosphate.Proc Natl Acad Sci U S A. 119(31):e2204407119. 

Lee Y, Phelps C, Huang T, Mostofian B, Wu L, Zhang Y, Tao K, Chang YH, Stork PJ, Gray JW, Zuckerman DM, Nan X. (2019) High-throughput, single-particle tracking reveals nested membrane domains that dictate KRasG12D diffusion and trafficking. eLife 8:e46393.

Rauen KA, Schoyer L, Schill L, Stronach B, Albeck J, Andresen BS, Cavé H, Ellis M, Fruchtman SM, Gelb BD, Gibson CC, Gripp K, Hefner E, Huang WYC, Itkin M, Kerr B, Linardic CM, McMahon M,... Stork PJS,... McCormick F. (2018) Proceedings of the fifth international RASopathies symposium: When development and cancer intersect. Am. J. Med. Genet. Part A 176(12):2924-2929.

Tillo SE, Xiong WH, Takahashi M, Miao S, Andrade AL, Fortin DA, Yang G, Qin M, Smoody BF, Stork PJS, Zhong H. (2017) Liberated PKA catalytic subunits associate with the membrane via myristoylation to preferentially phosphorylate membrane substrates. Cell Rep. 19(3):617-629.

Takahashi M, Li Y, Dillon TJ, Stork PJ. (2017) Phosphorylation of Rap1 by cAMP-dependent protein kinase (PKA) creates a binding site for KSR to sustain ERK activation by cAMP. J. Biol. Chem. 292(4):1449-1461.

Li Y, Dillon TJ, Takahashi M, Earley KT, Stork PJ. (2016) Protein kinase A-independent Ras protein activation cooperates with Rap1 protein to mediate activation of the extracellular signal-regulated kinases (ERK) by cAMP. J. Biol. Chem. 291(41):21584-21595.

Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJS, Kornev AP, Taylor SS, Shaw AS. (2013) Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154(5):1036-1046.
Takahashi M, Dillon TJ, Liu C, Kariya Y, Wang Z, Stork PJ. (2013) Protein kinase A-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. J. Biol. Chem. 288(39):27712-27723.

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(38):27646-27657.

Takahashi M, Li Y, Dillon TJ, Kariya Y, Stork PJS. (2017) Phosphorylation of the C-Raf N region promotes Raf dimerization. Mol. Cell Biol. 37(19):e00132-17. 

Takahashi M, Li Y, Dillon TJ, Stork PJ. (2017) Phosphorylation of Rap1 by cAMP-dependent protein kinase (PKA) creates a binding site for KSR to sustain ERK activation by cAMP. J. Biol. Chem. 292(4):1449-1461.
Hu J, Stites EC, Yu H, Germino EA, Meharena HS, Stork PJS, Kornev AP, Taylor SS, Shaw AS. (2013) Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154(5):1036-1046.
Mishra S, Smolik SM, Forte MA, Stork PJ. (2005) Ras-independent activation of ERK signaling via the Torso receptor tyrosine kinase is mediated by Rap1. Current Biol. 15(4):366-370. 

Schmitt JM, Stork PJ. (2002) PKA phosphorylation of Src mediates cAMP’s inhibition of cell growth via Rap1. Mol. Cell 9(1):85-94.

York RD, Molliver DC, Grewal SS, Stenberg PE, McCleskey EW, Stork PJ. (2000) Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1. Mol. Cell Biol. 20(21):8069-8083.

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(6676):622-626.

Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ. (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89(1):73-82.

Pan MG, Florio T, Stork PJ. (1992) G protein activation of a hormone-stimulated phosphatase in human tumor cells. Science 256(5060):1215-1217.