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2008 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 In 1993, Dr. Art Alberts received his Ph.D. in Physiology and Pharmacology at the University of California, San Diego School of Medicine, where he studied with Jim Feramisco. Dr. Alberts trained as a postdoctoral fellow from 1994 to 1997 with Richard Treisman at the Imperial Cancer Research Fund in London, England, where Dr. Treisman is the current Director. From 1997 through 1999, Dr. Alberts was an Assistant Research Biochemist in the laboratory of Frank McCormick at the University of California, San Francisco. In January 2000, Dr. Alberts joined VARI as a Scientific Investigator; he was promoted in 2006 to Senior Scientific Investigator. Also in 2006, he established and became the Director of the Flow Cytometry core facility. Staff Students Visiting Scientists Jun Peng, M.D. Kathryn Eisenmann, Ph.D. Holly Holman, Ph.D. Richard A. West, M.S. Susan Kitchen, B.S. Kellie Leali Aaron DeWard, B.S. Christopher Gorter Albert Rodriguez Katja Strunk Stephen Matheson, Ph.D. Brad Wallar, Ph.D. 6

VARI | 2008 Research Interests The Laboratory of Cell Structure and Signal Integration is devoted to understanding how defects in cellular architecture affect the progression to malignancy and support the tumorigenic platform. The driving hypothesis is that the cytoskeleton does not only structurally support cell morphology, division, and migration, but with its dynamic nature, it organizes intracellular signaling networks in order to effectively interpret proliferative and migratory responses to extracellular cues. On a molecular basis, we are interested in how cells build and control the cytoskeletal assembly machines and how these molecular machines work in concert within the cell. Through combined molecular, cellular, and genetic approaches, the ultimate goal of the lab is identifying defective nodes in the networks governing cytoskeletal remodeling in order to improve diagnosis and devising molecular tools to correct the defective circuits. Our focus is the role of Rho GTPases in signal transduction networks that control cell proliferation and motility. These highly conserved molecular switches act within growth factor responses by alternating between GTP- and GDP-bound forms. Upon GTP binding, Rho proteins undergo a conformational change that allows them to bind to and modulate the activity of effectors that remodel cell shape, drive motility and division, or alter gene expression patterns. One set of GTPase effector proteins acts as machines that assemble components of the cytoskeleton. The mammalian Diaphanous-related formin (mDia) family of actin-nucleating proteins initiate and control the elongation of new actin filaments. The three conserved mDia proteins (mDia1–3), along with insect Diaphanous protein and their budding yeast counterpart Bni1p, are canonical members of the formin family. With our discovery of one of the first formin proteins, mDia2, we have taken a leading role in their characterization. To study the role of mDia1 in vivo, the murine Drf1 gene was knocked out by conventional gene-targeting methods. Both Drf1 +/– and Drf1 –/– mice become progressively lympho- and myelodysplastic. Drf1-targeted mice are prone to developing tumors; cancers observed thus far include various leukemias, monocytosis, and plasmocytomas. Overall, mice lacking one or both Drf1 alleles phenocopy human myelodysplastic syndrome. Numerous defects in cytoskeletal remodeling have been observed in immune cells, including impaired T cell adhesion, migration, and the appearance of supernumerary centrosomes, which are indicative of failed cell division. These results were published in the Journal of Biological Chemistry and in Cancer Research. In the first paper with lead author Kate Eisenmann, entitled “T cell responses in mammalian Diaphanous-related formin mDia1 knock-out mice”, we demonstrated a role for mDia1 in normal immune cell function. Disruption of mDia1 leads to fewer T cells in secondary lymphoid organs in Drf1-null animals. T cell adhesion, migration, and proliferation upon activation were all impaired in T cells derived from Drf1-targeted mice. These results pointed to a crucial role for mDia1 in the dynamic regulation of the actin cytoskeleton in activated T cells. The second paper, with lead author Jun Peng, “Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian Diaphanous-related formin mDia1”, showed that mDia1 also plays an essential role in myelopoiesis. As animals age, they develop myeloproliferative defects in both the bone marrow and peripheral blood. These observations point to a crucial role of mDia1 in maintaining myeloid homeostasis, potentially by functioning as a tumor suppressor or susceptibility gene. 7

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