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2006 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Arthur S. Alberts, Ph.D. Laboratory of Cell Structure and Signal Integration 6 In 1993, Dr. Alberts received his Ph.D. in physiology and pharmacology at the University of California, San Diego, 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 Students Visiting Scientists Laboratory Staff Students Visiting Scientists Jun Peng, M.D. Yunju Chen, Ph.D. Kathryn Eisenmann, Ph.D. Holly Holman, Ph.D. Susan Kitchen, B.S. Aaron DeWard, B.S. Dagmar Hildebrand, B.S. Yaojian Liu, B.S. Stephen Matheson, Ph.D. Brad Wallar, Ph.D.

VARI | 2006 Research Interests The 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. Much of our work focuses on the role of cytoskeletal remodeling mediated by the formin family of actin-nucleating proteins. The formins are highly conserved proteins implicated in a diverse array of cellular functions, including the cytoskeletal remodeling events necessary for cytokinesis, bud formation in yeast, the establishment of cell/organelle polarity, and endocytosis. Formins have the ability to stabilize microtubules, which (like F-actin) are assembled by tightly controlled cycles of polymerization and depolymerization. The mDia formins act as Rho GTPase effectors during cytoskeletal remodeling. Rho GTPase binding to mDia amino-terminal GTPase-binding domains (GBDs) sterically hinders the adjacent Dia-inhibitory domain (DID) interaction with the carboxyl-terminal Diaautoregulatory (DAD) domain (Fig. 1). The release of DAD allows the adjacent FH2 domain to then nucleate and elongate nonbranched actin filaments. DAD, initially discovered as a region of homology shared between a phylogenetically divergent set of formin proteins, comprises a core motif (M-D-x-L-L-x-L) and an adjacent region of numerous basic residues (typically R-R-K-R) in the mDia family. 7 Figure 1. Figure 1. mDia proteins are autoregulated nucleators of actin. Autoinhibition is mediated by interaction between DID and DAD adjacent to the GBD and FH2 domains, respectively. Activated GTP-bound Rho proteins bind to the GBD where they interfere with DAD binding to DID. The free FH2 domains, which also function as dimerization interfaces, can then nucleate actin monomers and processively elongate actin filaments.

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