Philip D. King, Ph.D.

Genetic Analysis of Signal Transduction in Immune and Non-immune Cell Types in Health and Disease

Research in the King laboratory is aimed at understanding the nature of receptor-induced intracellular signaling pathways in immune and non-immune cell types. We are also interested in understanding how inherited and acquired mutations in genes that encode different signaling pathway components result in disease and how dysregulated signaling can be controlled to therapeutic benefit. The primary approach that we use to interrogate signaling pathways is conditional gene targeting in mice, which permits an understanding of receptor signal transduction in different physiological systems in the context of the whole animal. Hitherto, most of the genes that we have targeted encode regulators of the ubiquitous Ras signaling pathway. They include non-receptor protein tyrosine phosphatases, intracellular adapter proteins and Ras GTPase-activating proteins, which act upstream and downstream of the Ras small GTP-binding protein that is the nodal point in this pathway. The phenotypes that have emerged point to the complexity of mechanisms by which Ras activation is controlled and how these mechanisms vary in different cellular contexts. Furthermore, several of the generated mouse strains have emerged as important models of inherited genetic diseases in man that have yielded insights into mechanisms of disease pathogenesis. How the Ras pathway regulates lymphatic and blood vessel development and function in health and disease is currently a major focus of the laboratory. As part of these ongoing studies, we are making continued use of gene-targeted mouse strains as well as performing direct genetic and functional analyses upon tissue samples obtained from human patients.