The G-protein-coupled receptor (GPCR)-kinase-interacting proteins (GIT) 1 and 2 are multi-domain proteins involved in diverse cellular processes. In fibroblasts, GIT is thought to regulate focal adhesion (FA) turnover, cell spreading, and motility through interaction with various proteins. In T lymphocytes, GIT interacts with PIX (Pak-interacting Rac/Cdc42 guanine exchange factor) and PAK (p21-activated kinase) and forms a trimolecular complex. Our understanding of the physiological roles of GIT in T cells is very limited.
To determine the role of GIT1 and GIT2 in vivo, we generated GIT1- and GIT2- deficient mice. GIT1 is highly expressed in the brain, heart and testes. GIT2 is the major isoform expressed in hematopoietic cells. We found that GIT1 deficiency increased lethality, leading to perinatal death within 1-2 days after birth with a defect in brain development. GIT2-deficient mice were born healthy at normal Mendelian ratios. Interestingly, GIT2-deficient splenic T cells showed increased basal and chemokine-dependent migration. Furthermore, immature double positive thymocytes from GIT2-deficient mice showed increased basal and chemokine-induced migration. Since migration of thymocytes in the thymus has been tightly linked to their development, we crossed these mice to TCR transgenic mouse lines to better define the alterations in T-cell development and function by limiting compensation by repertoire selection. We found that the transition from the CD4 and CD8 double positive stage to CD4 single positive stage was greatly inhibited in the thymus of TCR transgenic GIT2-deficient mice. We are currently testing the hypothesis that GIT2 deficient-thymocytes have an altered migratory behavior leading to a defect in CD4 single positive thymocyte development.
*H.P. is supported by the Leukemia and Lymphoma Society Special Fellow Award.