Richard Firtel
e-mail: rafirtel@ucsd.edu |
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The Firtel laboratory focuses on the signal transduction pathways that control directional cell movement or chemotaxis and morphogenesis in eukaryotic cells. Chemotaxis is a basic property of many eukaryotic cells and plays critical roles in diverse biological pathways including wound healing, migration of leukocytes to sites of inflammation and bacterial infection, morphogenesis, and metastasis of a variety of cancer cell types. Chemotaxis is mediated by small molecule ligands (chemoattractants/chemokines) that interact with cell surface receptors to control downstream effector pathways. Cells are able to sense and respond to even weak chemoattractant gradients and to amplify this weak chemical gradient into steep intracellular gradients of signaling molecules. Cells then translate this into motor forces through the assembly of F-actin and myosin.
Over the past few years, great progress has been made in elucidating the molecular mechanisms controlling the ability of cells to sense and respond to chemical gradients. The Firtel lab and others have discovered that at the top of the signal transduction cascade is Ras and one of its effectors phosphatidylinositol 3-kinase (PI3K), components that are also essential for cell growth and survival in metazoan cells. The goal of the Firtel laboratory is to reveal the molecular mechanisms regulating these and other signaling pathways that enable cells to chemotax. Because most of these components are highly conserved evolutionarily in cells ranging from Dictyostelium amoebae to human leukocytes, the Firtel lab uses Dictyostelium as its experimental system because it allows one to employ a wide range of genetic as well as biochemical approaches to dissect these signaling pathways. These methods are combined with in vivo, real-time analysis of GFP fusions of signaling proteins in living cells to understand the spatio-temporal changes of these proteins in response to directional signals. These diverse approaches have allowed the Firtel lab and others to formulate models of the signal transduction pathways that control chemotaxis that are applicable to human leukocytes as well as Dictyostelium cells.
Chemotaxis of wild-type cells to cAMP emitted from a pipette.
Co-activation of Ras and PI3K at the leading edge of chemotaxing cells using real-time reporters
Selected publications:
Sobko, A., H. Ma, and R A. Firtel (2002). Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis. Devel. Cell 2:745-756.
Funamoto, S., R. Meili, S. Lee, L. Parry and R.A. Firtel (2002). Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109:611-623.
Sasaki, A.T., C. Chun, K. Takeda and R.A. Firtel (2004). Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement. J. Cell Biol. 167:505-518.
Park, K.C., F. Rivero, R. Meili, S. Lee, F. Apone and R.A. Firtel (2004). Rac regulation of chemotaxis and morphogenesis in Dictyostelium. EMBO J. 23:4177-4189.
Mendoza, M.C., F. Du, N. Iranfar, N. Tang, H. Ma, W.F. Loomis and R.A. Firtel (2005). Loss of SMEK, a novel, conserved protein, suppresses mek1 null cell polarity, chemotaxis, and gene expression defects. Mol. Cell. Biol. 2:7839-7853.
Lee, S., F.I. Comer, A. Sasaki, I.X. McLeod, Y. Duong, K. Okamura, J.R. Yates III, C.A. Parent and R.A. Firtel (2005). TOR Complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 16:4572-4583.
Jeon, T., D. Lee, S. Merlot, K. Takeda, G. Weeks and R.A. Firtel (2007). Rap1 controls cell adhesion and cell motility through the regulation of myosin II. J. Cell Biol., 178:1021-1033.
Mendoza, M.C., E.O. Booth, G. Shaulsky and R.A. Firtel (2007). MEK1 and Protein Phosphatase 4 Coordinate Dictyostelium Development and Chemotaxis. Mol. Cell Biol. in press.
Kosuke Takeda, Atsuo T. Sasaki, Hyunjung Ha, Hyun-A Seung, and Firtel, R. A. (2007). Role of PI3 kinases in chemotaxis in Dictyostelium. J. Biol. Chem. in press.
