Alan F. "Rick" Horwitz, PhD
Regulation of cell adhesion dynamics and cell migration of normal and cancer cells
The Horwitz lab is taking an eclectic approach to studying adhesion dynamics in the migration of normal and cancer cells. The unifying theme is the mechanisms that regulate the formation and disassembly of adhesions during migration. Recent studies have focused on a set of critical molecules including: integrin, paxillin, FAK, Pix, PAK, and GIT1, and significant progress has been made on several fronts. Quantitative assays for adhesion turnover have been developed and used to define a signaling pathway that regulates adhesion disassembly. The key regulatory components are: FAK, Src, p130CAS, paxillin, ERK and MLCK. Another major development is a collaboration with the Don Hunt lab to develop methods for the global identification of utilized phosphorylation sites using mass spectrometry. One of these sites has led them to a key, paxillin based, regulatory mechanism for the formation of protrusions and adhesions. This has also led them to the identification of a new class of adhesions that reside at the cell front and drive migration; these adhesions are particularly prominent in highly motile, metastatic cells. The lab is collaborating to develop correlation microscopy for studying adhesion dynamics and signaling in migrating cells. Methods are now in place to produce high resolution maps of protein concentration, diffusion, flow and binding kinetics, and interactions during migration. This approach has been already been used to produce highly quantitative data from scanning confocal images of migrating cells. Finally, the adapter molecule, GIT has been a focus of intensive study. It forms and localizes a signaling PIX/PAK/Rac signaling module to the leading edge and new adhesions in migrating cells and appears to be a key regulator of protrusion formation and adhesion.