Mechanisms Of The Immune Response And Programmed Cell Death GIT2 Regulation

G protein-coupled receptor kinase interactors (GIT1and GIT2) subfamily belong to ARF-GAP family. GITs are multidomain ubquitous proteins involved in diverse functions. The encoding sequences of GIT1and GIT2are conserved. There are three important domains of GIT proteins. The ARF-GAP domain in the N terminal of GITs regulates the membrane trafficking between the plasma membrane and endosomes. The SH domain in the middle of GITs controls the activity of small G protein Rac family through binding to PIX. Furthermore, we found that the SH domain inhibits the ubiquitination of TRAF6and NF-κB activity. Paxillin binding domain in the C terminal of GITs regulates cellular skeleton and motility.Although GIT1and GIT2proteins are highly similar and have same domain structure, the distribution of them is different in mouse tissues. The GIT1is restricted to cells lining blood vessels, bronchi and bile ducts, whereas GIT2is expressed in most cells in the liver and lung. GIT1is highly expressed in the nervous system and Git1-/-mice showed ADHD-like phenotypes with traits including hyperactivity and impaired learning and memory. GIT2is highly expressed in the immune system, which implicates the important functions of GIT2in immunity. Git2-/-mice often develop splenomegaly and highly susceptible to fungi infection. Neutrophil direction and positive selection of thymocyte of Git2-/-mice was impaired. We showed that Git2-/-mice developed immunological abnormalities in the lamina propria of colon and severed blepharitis. Moreover, Git2-/-mice were more susceptible to E.coli or endotoxin shock challenge.Inflammatory bowel disease (IBD) results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. The genetic mutations of the immune related genes and epithelial dysfunction leads to IBD. TLR signaling plays a critical role in regulation of the IBD and Tlr4-/-mice or Myd88-/-mice were more susceptible to DSS-induced colitis. Here we showed that Git2-/-mice were more susceptible to DSS-induced colitis. The susceptibility of Git2deficiency mice to DSS-induced colitis depended on TLR signaling. The expression of GIT2in the hematopoietic cells and local cells of the colonic mucosa plays a critical role in protection against DSS-induced colitis.Post-translational modifications including ubiquitination, phosphorylation, acetylation and methylation, are the important ways to regulate the signaling pathway. GIT proteins are substrates of the non-receptor tyrosine kinase FAK and Src. Phosphorylation of GIT2is important for directing cell migration to PDGF in fibroblasts, while GIT1is similarly required for EGF-dependent vascular smooth muscle cell migration. Here we show that GIT2interacts with Caspase-7and is a substrate of Caspase-7. The cleavage sites are in the N terminal of GIT2.NLR related inflammasome play a critical role in regulation of carcinogenesis. Actived inflammasome suppressed NK cell and T cell mediated immunosurveillance。 IL-1β and IL-18improved the angiogenesis and invasiveness of tumor cells. GIT1is required for cellular transformation. Its expression is frequently enhanced in human cervical cancers. We found that GIT2is highly expressed in human colon cancers. Thus, GIT2might be a candidate biomarker to dignosis the colon cancer.