Philip J Stork, MD

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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.

Summary of Current Research

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.

Selected Publications

"Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes," American Journal of Physiology - Heart and Circulatory Physiology (Vol: 307, Issue: 8, Page H1216-H1225) - 2014

"Allosteric activation of functionally asymmetric RAF kinase dimers," Cell (Vol: 154, Issue: 5, Page 1036-1046) - 2013

"B-Raf is required for positive selection and survival of DP cells, but not for negative selection of SP cells," International Immunology (Vol: 25, Issue: 4, Page 259-269) - 2013

"N terminus of ASPP2 binds to Ras and enhances Ras/Raf/MEK/ERK activation to promote oncogene-induced senescence," Proceedings of the National Academy of Sciences of the United States of America (Vol: 110, Issue: 1, Page 312-317) - 2013

"Protein kinase a-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration," Journal of Biological Chemistry (Vol: 288, Issue: 39, Page 27712-27723) - 2013



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