Philip Lapinski, Ph.D.
Philip King, Ph.D.
Ras is a small G-protein that is involved in numerous cell signaling pathways. Ras acts as a molecular switch, active when bound to GTP and inactive when bound to GDP. Two classes of proteins modulate Ras activity, including guanine-nucleotide exchange factors (GEFs) which activate Ras, and GTPase activating proteins (GAPs) that inactivate Ras. In T cells, the GEFs which activate Ras upon T cell receptor stimulation are known. In contrast, the GAPs which downregulate Ras activity in T cells are less well studied. We have focused on RASA1, which is the first GAP to be characterized at the molecular level. A null allele for the rasa1 gene has been generated, but mice homozygous for this gene die during embryonic development of a vascular defect. This makes the use of the null allele to study T cells extremely difficult. To circumvent the problem of embryonic cell death, we have generated a conditional rasa1 allele in mice. By crossing these mice with transgenic mice expressing Cre recombinase under the control of a T cell-specific promoter, we have been able to delete RASA1 expression specifically in this cell type. In addition, we have crossed the conditional rasa1 allele to transgenic mice expressing a drug-inducible form of Cre, and achieved nearly complete deletion of RASA1 in all tissues of adult mice. Using these systems, we have shown that RASA1 plays an important role in T cell development and function. We have also shown that RASA1 is critical in the maintenance of lymphatic channels in adult mice. My research currently focuses on determining the molecular mechanisms responsible for the observed phenotypes.
Lapinski P.E., Oliver J.A., and King P.D. 2009. The TSAd family of adapter proteins. Immunol. Rev. In Press.
Lapinski PE, Kamen LA, Hughes ED, Saunders TL and King PD. Genetic analysis of SH2D4A, a novel adapter protein related to TSAd and ALX, reveals a redundant function in T cells. J. Immunol., Aug 2008; 181: 2019 - 2027.
Lapinski PE, Bauler TJ, Brown EJ, Hughes ED, Saunders TL, and King PD. In press. Generation of Mice with a Conditional Allele of the p120 Ras GTPase-activating Protein (RasGAP). Genesis, Dec 2007; 45(12): 762-
Perria CL, Rajamanickam V, Lapinski PE, and RaghavanM. 2006. Catalytic Site Modifications of TAP1 and TAP2 and Their Functional Consequences J. Biol. Chem., 281: 39839 - 39851.
Marti F,. Garcia GG, Lapinski PE, MacGregor JN, and KingPD. 2006. Essential role of the T cell–specific adapter protein in the activation of LCK in peripheral T cells J. Exp. Med, 203: 281 - 287.
Lapinski PE, MacGregor JN, Marti F, and King PD. 2006. The T cell-specific adapter protein functions as a regulator of peripheral but not central immunological tolerance. Adv Exp Med Biol, 584: 73-87.
Yang T, Lapinski PE, Zhao H, Zhou Q, Zhang H, Raghavan M, Liu Y, Zheng P. 2005. A rare transporter associated with antigen processing polymorphism overpresented in HLA low colon cancer reveals the functional significance of the signature domain in antigen processing. Clin Cancer Res. 11(10):3614-23.
Marti F, Lapinski PE, King PD. Sh2d2a. AfCS-Nature Molecule Pages (2005). (doi:10.1038/mp.a002075.01)
Marti F, Lapinski PE, King PD. 2005. The emerging role of the T cell-specific adaptor (TSAd) protein as an autoimmune disease-regulator in mouse and man. Immunol Lett. 97(2):165-70.
Lapinski PE, Raghuraman G, Raghavan M. 2003. Nucleotide interactions with membrane-bound transporter associated with antigen processing proteins. J Biol Chem. 278(10):8229-37.
Raghuraman G, Lapinski PE, Raghavan M. 2002. Tapasin interacts with the membrane-spanning domains of both TAP subunits and enhances the structural stability of TAP1 x TAP2 Complexes. J Biol Chem. 277(44):41786-94.
Mancino L, Rizvi SM, Lapinski PE, Raghavan M. 2002. Calreticulin recognizes misfolded HLA-A2 heavy chains. Proc Natl Acad Sci U S A. 99(9):5931-6.
Arora S, Lapinski PE, Raghavan M. 2001. Use of chimeric proteins to investigate the role of transporter associated with antigen processing (TAP) structural domains in peptide binding and translocation. Proc Natl Acad Sci U S A. 98(13):7241-6.
Lapinski PE, Neubig RR, Raghavan M. 2000. Walker A lysine mutations of TAP1 and TAP2 interfere with peptide translocation but not peptide binding. J Biol Chem. 276(10):7526-33.
Lapinski PE, Miller GG, Tampe R, Raghavan M. 2000. Pairing of the nucleotide binding domains of the transporter associated with antigen processing. J Biol Chem. 275(10):6831-40.
Honors and Awards: