Biomedical Sciences Graduate Program | University of California, San Francisco

For more than 25 years, my lab focused on trimeric G proteins and G protein coupled receptors (GPCRs). About five years ago, however, I began studying the twin problems of polarity and chemotaxis in human neutrophils -- leukocytes whose ability to crawl toward sites of tissue inujury plays a key role in host defense. Using an experimental chemotaxis model in a human promyelocytic leukemia line, my laboratory found that chemoattractants like f-Met-Leu-Phe (fMLP) cause 3'-phosphoinositide lipids (PI3Ps) to accumulate at the leading edge of neutrophil-like HL-60 cells. This response is necessary for activation of two Rho GTPases, Rac and Cdc42, and for fMLP-dependent formation of F-actin-containing pseudopods. PI3Ps act both up-and downstream of Rho GTPases and actin, forming a positive feedback loop that is necessary for protrusion and movement of the leading edge. In addition, cell-surface receptors for fMLP and other attractants trigger polarity by activating opposed "frontness" and "backness" pathways, which are mediated (at the front) by Gi, PI3Ps, Rac, and polymerized actin and (at the back) by G12/13, Rho, ROCK, and mysoin-based contraction. Opposed actions of divergent frontness and backness signals explain how fMLP induces "self-organizing" polarity, in which a pseudopod highly sensitive to attractant cleanly demarcates itself from less sensitive myosin-enriched domains at the back and sides. The lab is now focusing most of its effort on the neutrophil "compass," which interprets gradients of chemoattractant. The compass mechanism appears to involve a third Rho GTPase, Cdc42, as well as PI3Ps.