Areas of Interest
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.
Charpentier JC, Chen D, Lapinski PE, Turner J, Grigorova I, Swanson JA, King PD Macropinocytosis drives T cell growth by sustaining the activation of mTORC1. https://www.nature.com/articles/s41467-019-13997-3
Nat. Commun. 2020 Jan 10; 11, 180 doi:10.1038/s41467-019-13997-3
Chen D, Teng JM, North PE, Lapinski PE, King PD. RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development. J Clin Invest. 2019 Jun 11;130:3545-3561. doi: 10.1172/JCI124917. PubMed PMID: 31185000; PubMed Central PMCID: PMC6715364.
Lapinski PE, Doosti A, Salato V, North P, Burrows PE, King PD. Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet. 2018 Jan;61(1):11-16. doi: 10.1016/j.ejmg.2017.10.004. Epub 2017 Oct 9. PubMed PMID: 29024832; PubMed Central PMCID: PMC5766414.
Lapinski PE, Lubeck BA, Chen D, Doosti A, Zawieja SD, Davis MJ, King PD. RASA1 regulates the function of lymphatic vessel valves in mice. J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22. PubMed PMID: 28530642; PubMed Central PMCID: PMC5490778.
Lubeck BA, Lapinski PE, Oliver JA, Ksionda O, Parada LF, Zhu Y, Maillard I, Chiang M, Roose J, King PD. Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia. J Immunol. 2015 Jul 1;195(1):31-5. doi: 10.4049/jimmunol.1402639. Epub 2015 May 22. PubMed PMID: 26002977; PubMed Central PMCID: PMC4475412.
Lubeck BA, Lapinski PE, Bauler TJ, Oliver JA, Hughes ED, Saunders TL, King PD. Blood vascular abnormalities in Rasa1(R780Q) knockin mice: implications for the pathogenesis of capillary malformation-arteriovenous malformation. Am J Pathol. 2014 Dec;184(12):3163-9. doi: 10.1016/j.ajpath.2014.08.018. Epub 2014 Oct 3. PubMed PMID: 25283357; PubMed Central PMCID: PMC4258499.
Lapinski PE, Meyer MF, Feng GS, Kamiya N, King PD. Deletion of SHP-2 in mesenchymal stem cells causes growth retardation, limb and chest deformity, and calvarial defects in mice. Dis Model Mech. 2013 Nov;6(6):1448-58. doi: 10.1242/dmm.012849. Epub 2013 Sep 25. PubMed PMID: 24077964; PubMed Central PMCID: PMC3820267.
Lapinski PE, Kwon S, Lubeck BA, Wilkinson JE, Srinivasan RS, Sevick-Muraca E, King PD. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest. 2012 Feb;122(2):733-47. doi: 10.1172/JCI46116. Epub 2012 Jan 9. PubMed PMID: 22232212; PubMed Central PMCID: PMC3266774.