Our laboratory focuses on the signal transduction pathways and the mechanics that control directional cell movement, or chemotaxis, and morphogenesis of 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 a weak chemical gradient into a steep intracellular gradient of signaling molecules. Cells then translate this into changes in the cytoskeleton that control the mechanical forces that drive cell movement.
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. My laboratory 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. Our goal 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 primary 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 elucidate the basic principles by which signal transduction pathways control directional sensing and chemotaxis that apply to human leukocytes as well as Dictyostelium cells.
A major unanswered question in cell motility is how the signaling pathways and the reorganizations of the cytoskeleton function together to control cell movement. In collaboration with the groups of Juan Lasheras and Juan Carlos del Alamo in the Department of Mechanical and Aerospace Engineering, we have developed quantitative approaches to examine the time evolution of the traction forces that mediate each stage of the cell motility cycle. We have made the novel finding that amoeboid cell movement is controlled by a complex interplay between lateral and normal (vertical) forces mediated by cortical tension controlled through the lateral cell cortex as well as the more “classic” F-actin/myosin-mediated axial forces. We have achieved this by integrating the biochemical and mechanical measurements of cell motility and obtained the quantitative information necessary to connect specific biochemical and signaling processes to the physical events regulating the mechanical forces controlling cell motility and, in do so, understand how cells move. In collaboration with Wouter-Jan Rappel, Alex Groisman, and Bill Loomis, we are attempting to mathematically model the signaling events controlling cell polarization.
Rick Firtel was an undergraduate in Biology and Chemistry and Rufus Choate Scholar at Dartmouth College (1966) and received his PhD at Caltech in James Bonner’s laboratory as an NSF fellow (1971). Rick did his postdoctoral work with Harvey Lodish at MIT as a Helen Hay Whitney Foundation Fellow and joined the faculty at UCSD in 1973. He has been the recipient of an American Cancer Society Faculty Research Award, an International Union Against Cancer Fellowship, a Japanese Society for the Promotion of Sciences Fellowship, and a John Simon Guggenheim Fellowship. He has served as Director of the Center for Molecular Genetics (1995-2004), Chair of the Section of Cell and Developmental Biology (1999-2006), and Associate Dean of Biological Sciences (2008-present).