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2005 Scientific Report

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2005

2005 VARI Scientific Retreat 8

Laboratory of Cell Structure and Signal Integration Arthur S. Alberts, Ph.D. Dr. Alberts received his Ph.D. in physiology and pharmacology at the University of California, San Diego, in 1993, where he studied with James Feramisco. From 1994 to 1997, he served as a postdoctoral fellow in Richard Treisman’s laboratory at the Imperial Cancer Research Fund in London, England. From 1997 through 1999, he was an Assistant Research Biochemist in the laboratory of Frank McCormick at the Cancer Research Institute, University of California, San Francisco. Dr. Alberts joined VARI as a Scientific Investigator in January 2000. Staff Art Alberts, Ph.D. Jun Peng, M.D. Yunju Chen, Ph.D. Kathryn Eisenmann, Ph.D. Holly Holman, Ph.D. Susan Kitchen, B.S. Laboratory Members Students Aaron DeWard, B.S. Yaojian Liu, B.S. Katharine Collins Visiting Scientists Stephen Matheson, Ph.D. Brad Wallar, Ph.D. Research Interests T he actin cytoskeleton is a dynamic, tightly regulated protein network that plays a crucial role in mediating diverse cellular processes including cell division, migration, endocytosis, vesicle trafficking, and cell shape. The research focus of the lab is the genetics and molecular biology of the Rho family of small GTPases and their effectors, which together control multiple aspects of cytoskeletal dynamics. The guiding hypothesis of the laboratory is that cytoskeletal dynamics defines the what, where, and how of signal transduction pathways, control responses to growth factors, and other extracellular cues, and that defects in these tightly controlled dynamics can contribute to cancer pathophysiology. Support for this hypothesis is observed in human cancers that carry mutations in genes encoding regulators of Rho GTPase activity. Ultimately, our goal is to exploit our understanding of the mechanics of GTPase-effector relationships in order to develop anti-cancer therapeutics. PAK1 negatively regulates the activity of the Rho exchange factor NET1 Rho GTPases act as molecular switches in cells, alternating between on and off states while bound to GTP and GDP nucleotides, respectively. The activated, GTP-bound proteins preferentially interact with numerous autoregulated downstream effector proteins. Rho GTPases are activated by Rho guanine nucleotide exchange factors (Rho GEFs), one of which is the neuroepithelioma transforming gene 1 (NET1). Recently it was demonstrated that wild-type NET1 is localized in the nucleus and that truncation of the amino terminus results in relocalization of a fraction of the NET1 to the cytoplasm. This is at least partially due to the elimination of two putative nuclear localization signals within the amino terminus. Thus, NET1 activity is regulated at least in part through subcellular localization. Rho family members can modulate the activity of other Rho proteins. The protein kinase PAK1 down-regulates the activity of the RhoAspecific GEF NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues reduces the activity of NET1 as an exchange factor in vitro, as well as its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody, PAK1 can be shown to phosphorylate NET1 on serine 152 in cells, and Rac1, which activates PAK1, stimulates serine 152 phosphorylation in a PAK1-dependent manner. Furthermore, coexpression of constitutively active PAK1 inhibits NET1 stimulation of actin polymerization only when serines 152 and 153 are present. These observations provide a novel mechanism for the control of RhoA activity. 9

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