Alternative titles; symbols
HGNC Approved Gene Symbol: GIT1
Cytogenetic location: 17q11.2 Genomic coordinates (GRCh38): 17:29,573,475-29,589,648 (from NCBI)
Using bovine GRK2 (109635) as bait in a yeast 2-hybrid screen, Premont et al. (1998) cloned rat Git1 from a brain cDNA library. The deduced 770-amino acid protein contains an N-terminal zinc finger-like motif, followed by ankyrin (see 600465) repeats and a C-terminal GRK-interacting domain. Northern blot analysis of rat tissues detected wide expression of a 4.0-kb Git1 transcript, with highest expression in testis and lowest expression in liver and spleen.
Premont et al. (2000) reported that the deduced 761-amino acid human GIT1 protein contains an N-terminal ARFGAP (see 608377) domain, followed by ankyrin repeats.
By screening for clones encoding proteins expressed at focal adhesions or cytoskeletal structures in transfected fibrosarcoma cells, followed by screening a fetal brain cDNA library, Manabe et al. (2002) cloned GIT1. Following the ankyrin repeats, GIT1 contains a central PIX (see 300267)-binding domain and a C-terminal paxillin (PAX; 602505)-binding domain.
Premont et al. (1998) found that overexpression of rat Git1 in human embryonic kidney cells coexpressing beta-2-adrenergic receptor (ADRB2; 109690) led to reduced ADRB2 signaling and increased receptor phosphorylation due to reduced receptor internalization and resensitization. These cellular effects of Git1 required its intact ARFGAP activity.
Premont et al. (2000) found that endogenous COS cell paxillin immunoprecipitated with human GIT1 following transfection.
Manabe et al. (2002) demonstrated that GIT1 localized to 3 distinct subcellular compartments, including focal adhesions, cytoplasmic complexes, and membrane protrusions. Paxillin, PIX, and PAK (see 602590) all colocalized with GIT1 in cytoplasmic complexes. The complexes were motile and appeared to mediate delivery of components to and from adhesions as they assembled and disassembled. The paxillin-binding domain of GIT1 was required to recruit GIT1 to focal adhesions and the leading edge of the lamellipodia. The central ankyrin repeats and the PIX-binding domain were required to target GIT1 to the cytoplasmic complexes. Expression of GIT1 or its C-terminal paxillin-binding domain increased the rate of migration and the size and frequency of protrusions; PAK association was necessary for this effect.
Zhang et al. (2003) found that Git1 was enriched in rat hippocampal neurons at both pre- and postsynaptic terminals. It was targeted to these sites by sequences located between the PIX- and PAX-binding domains. Disruption of the synaptic localization of Git1 by a dominant-negative mutant resulted in altered spine morphology and synapse formation. Rac (see 602048) acted downstream of Git1 in affecting synapse morphology.
Role in Huntington Disease
Goehler et al. (2004) generated a protein-protein interaction network for Huntington disease (HD; 143100) and identified GIT1 as a protein that interacts directly with huntingtin (htt). Using a cell-based assay, they found that coexpression of GIT1 and HD169Q68, an aggregation-prone N-terminal htt fragment with a 68-residue polyglutamine tract, increased the amount of htt aggregates 3-fold compared with expression of HD169Q68 alone. N-terminally truncated GIT1 was a more potent enhancer of htt aggregation than the full-length protein. Mutation analysis indicated that the C terminus of GIT1 interacted with the N terminus of htt. HD169Q68 distributed to the cytoplasm of transfected human embryonic kidney cells, but coexpression with GIT1 resulted in relocalization of HD169Q68 to membranous structures and accumulation of protein aggregates. In wildtype mice, Git1 distributed diffusely in neurons throughout the brain, but in a mouse model of HD, Git1 immunoreactivity was also present in large nuclear and cytoplasmic puncta containing htt aggregates. In normal human brain, GIT1 migrated at an apparent molecular mass of 95 kD. However, in HD brains, expression of the 95-kD protein was reduced, and prominent GIT1 C-terminal fragments of 25 to 50 kD were also detected. Goehler et al. (2004) concluded that accumulation of C-terminal GIT1 fragments in HD may contribute to disease pathogenesis.
By EST database analysis and radiation hybrid analysis, Premont et al. (1998) mapped the GIT1 gene to chromosome 17p11.2. However, Gross (2020) mapped the GIT1 gene to chromosome 17q11.2 based on an alignment of the GIT1 sequence (GenBank AF124490) with the genomic sequence (GRCh38).
For a discussion of a possible association between variation in the GIT1 gene and attention deficit-hyperactivity disorder, see 608904.
Won et al. (2011) found that Git1 -/- mice had decreased survival compared to wildtype, with about 50% of mutant mice dying postnatally. Mice that survived demonstrated ADHD-like phenotypic traits (see ADHD, 143465), including hyperactivity, impaired learning and memory, and enhanced theta rhythms, all of which were reversed by amphetamines. These abnormal behaviors decreased with age. Git1 +/- mice did not differ from wildtype. Studies of brain tissue from Git1 -/- mice showed decreased Rac1 (602048) signaling, as evidenced by decreased Pak3 (300142) phosphorylation, as well as a substantial reduction in inhibitory presynaptic input. These results suggested that the balance between excitation and inhibition in CA1 pyramidal neurons was shifted toward excitation as a result of limited inhibitory presynaptic input. Won et al. (2011) concluded that Git1 deficiency in mice can serve as a model of the psychostimulant-responsive ADHD-like phenotype.
Goehler, H., Lalowski, M., Stelzl, U., Waelter, S., Stroedicke, M., Worm, U., Droege, A., Lindenberg, K. S., Knoblich, M., Haenig, C., Herbst, M., Suopanki, J., and 12 others. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Molec. Cell 15: 853-865, 2004. Note: Erratum: Molec. Cell 19: 287 only, 2005. [PubMed: 15383276] [Full Text: https://doi.org/10.1016/j.molcel.2004.09.016]
Gross, M. B. Personal Communication. Baltimore, Md. 7/24/2020.
Manabe, R., Kovalenko, M., Webb, D. J., Horwitz, A. R. GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration. J. Cell Sci. 115: 1497-1510, 2002. [PubMed: 11896197] [Full Text: https://doi.org/10.1242/jcs.115.7.1497]
Premont, R. T., Claing, A., Vitale, N., Freeman, J. L. R., Pitcher, J. A., Patton, W. A., Moss, J., Vaughan, M., Lefkowitz, R. J. Beta-2-adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc. Nat. Acad. Sci. 95: 14082-14087, 1998. [PubMed: 9826657] [Full Text: https://doi.org/10.1073/pnas.95.24.14082]
Premont, R. T., Claing, A., Vitale, N., Perry, S. J., Lefkowitz, R. J. The GIT family of ADP-ribosylation factor GTPase-activating proteins: functional diversity of GIT2 through alternative splicing. J. Biol. Chem. 275: 22373-22380, 2000. [PubMed: 10896954] [Full Text: https://doi.org/10.1074/jbc.275.29.22373]
Won, H., Mah, W., Kim, E., Kim, J.-W., Hahm, E.-K., Kim, M.-H., Cho, S., Kim, J., Jang, H., Cho, S.-C., Kim, B.-N., Shin, M.-S., Seo, J., Jeong, J., Choi, S.-Y., Kim, D., Kang, C., Kim, E. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nature Med. 17: 566-572, 2011. [PubMed: 21499268] [Full Text: https://doi.org/10.1038/nm.2330]
Zhang, H., Webb, D. J., Asmussen, H., Horwitz, A. F. Synapse formation is regulated by the signaling adaptor GIT1. J. Cell Biol. 161: 131-142, 2003. [PubMed: 12695502] [Full Text: https://doi.org/10.1083/jcb.200211002]