Philip D. King
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.
Lapinski P.E., Qiao Y., Chang C-H. and King P.D. 2011. A role for p120 RasGAP (RASA1) in thymocyte positive selection and survival of naive T cells in mice. J. Immunol. 187:151-163.
Bauler T.J., Kamiya N., Lapinski P.E., Langewisch E., Mishina Y., Wilkinson J.E., Feng G.S. and King P.D. 2011. Development of severe skeletal defects in induced SHP-2-deficient adult mice: a model of skeletal malformation in humans with SHP-2 mutations. Dis. Model. Mech. 4:228-239.
Lapinski P.E., Kwon S., Lubeck B.A., Wilkinson J.E., Srinivasan, S., Sevick-Muraca E. and King P.D. 2012. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J. Clin. Invest.122: 733-747.
Burrows P.E., Gonzalez-Garay M., Rasmussen J.C., Aldrich M.E., Gulloid R., Maus E.A., Fife C.E., Kwon S., Lapinski P.E., King P.D. and Sevick-Muraca E.M. 2013. Lymphatic abnormalities are associated with RASA1 mutations in mouse and man. Proc. Natl. Acad. Sci. USA. 110:8621-8626.
King P.D., Lubeck B.A. and Lapinski P.E. 2013. Non-redundant functions for Ras-GTPase-activating proteins in tissue homeostasis. Science Signaling 6:1-11.
Lapinski P.E., Meyer M.F., Feng G.S., Kamiya N. and King P.D. 2013. Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity, and calvarial defects in mice. Dis. Model Mech. 6:1448-58.
Oliver J.A., Lapinski P.E., Lubeck B.A., Turner J.S., Parada L.F., Zhu Y. and King P.D. 2013 The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes. Mol. Immunol. 2013 55:292-302.
Kamiya N., Kim H.K. and King P.D. 2014. Regulation of bone and skeletal development by the SHP-2 protein tyrosine phosphatase. Bone. 2014. 69:55-60.
Sevick-Muraca E.M. and King P.D. 2014. Lymphatic vessel abnormalities arising from disorders of Ras signal transduction. Trends Cardiovasc. Med. 2014. 24:121-7.
Lubeck B.A., Lapinski P.E., Bauler T.J., Oliver J.A., Hughes E.D., Saunders T.L. and King P.D. 2014. Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. Am. J. Pathol. 184:3163-9.
Lubeck B.A., Lapinski P., Oliver J.A., Ksionda O., Parada L.F., Zhu Y., Maillard I., Chiang M., Roose J. and King P.D. 2015. Co-deletion of the Ras GTPase-activating proteins Neurofibromin 1 (NF1) and p120 RasGAP (RASA1) in T cells results in the development of T cell acute lymphoblastic leukemia. J. Immunol. Cutting Edge (in press).