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Richard Firtel e-mail: rafirtel@ucsd.edu |
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Our 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 and 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. We and others have discovered that Ras lies at the top of the signal transduction cascade leading to chemotaxis. We demonstrated that Ras controls chemotaxis through the activation of phosphatidylinositol 3-kinase (PI3K) and Tor Complex 2, which are also essential for cell growth and survival in metazoan cells. The goal of the 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, we use Dictyostelium as our experimental system, which allows us 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 us and others to formulate models of the signal transduction pathways controlling chemotaxis that are applicable to human leukocytes as well as Dictyostelium cells.
In collaboration with Juan Lasheras’ group in the Department of Mechanical and Aerospace Engineering, we are developing quantitative approaches to examine the evolution of the traction forces that mediate each stage of the cell motility cycle. These approaches involve using conditional and phase statistics as well as Proper Orthogonal Decomposition (POD) analysis to integrate the biochemical and mechanical measurements of cell motility and obtain the quantitative information necessary to connect specific biochemical processes to each of the physical events during cell motility. In collaboration with the groups of Herbert Levine, Wouter-Jan Rappel, and Alex Groisman in the Department of Physics and Bill Loomis in the Division of Biological Sciences, we are attempting to mathematically model the signaling events controlling cell polarization.
Co-activation of Ras and PI3K at the leading edge of chemotaxing cells using real-time reporters
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.
