ID GIT1_MOUSE Reviewed; 770 AA. AC Q68FF6; DT 13-SEP-2005, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2004, sequence version 1. DT 24-JAN-2024, entry version 180. DE RecName: Full=ARF GTPase-activating protein GIT1; DE Short=ARF GAP GIT1; DE AltName: Full=G protein-coupled receptor kinase-interactor 1; DE AltName: Full=GRK-interacting protein 1; GN Name=Git1; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP INTERACTION WITH TGFB1I1. RX PubMed=12153727; DOI=10.1093/oxfordjournals.jbchem.a003222; RA Nishiya N., Shirai T., Suzuki W., Nose K.; RT "Hic-5 interacts with GIT1 with a different binding mode from paxillin."; RL J. Biochem. 132:279-289(2002). RN [4] RP FUNCTION. RX PubMed=12695502; DOI=10.1083/jcb.200211002; RA Zhang H., Webb D.J., Asmussen H., Horwitz A.F.; RT "Synapse formation is regulated by the signaling adaptor GIT1."; RL J. Cell Biol. 161:131-142(2003). RN [5] RP INTERACTION WITH SCRIB, AND TISSUE SPECIFICITY. RX PubMed=15182672; DOI=10.1016/j.cub.2004.05.051; RA Audebert S., Navarro C., Nourry C., Chasserot-Golaz S., Lecine P., RA Bellaiche Y., Dupont J.-L., Premont R.T., Sempere C., Strub J.-M., RA Van Dorsselaer A., Vitale N., Borg J.-P.; RT "Mammalian Scribble forms a tight complex with the betaPIX exchange RT factor."; RL Curr. Biol. 14:987-995(2004). RN [6] RP INTERACTION WITH MAPK1 AND MAPK3, MUTAGENESIS OF 420-MET--ALA-475, AND RP SUBCELLULAR LOCATION. RX PubMed=15923189; DOI=10.1074/jbc.m502271200; RA Yin G., Zheng Q., Yan C., Berk B.C.; RT "GIT1 is a scaffold for ERK1/2 activation in focal adhesions."; RL J. Biol. Chem. 280:27705-27712(2005). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-563, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [8] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain; RX PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200; RA Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.; RT "Comprehensive identification of phosphorylation sites in postsynaptic RT density preparations."; RL Mol. Cell. Proteomics 5:914-922(2006). RN [9] RP INTERACTION WITH YWHAZ, AND TISSUE SPECIFICITY. RX PubMed=16959763; DOI=10.1074/mcp.m600147-mcp200; RA Angrand P.O., Segura I., Voelkel P., Ghidelli S., Terry R., Brajenovic M., RA Vintersten K., Klein R., Superti-Furga G., Drewes G., Kuster B., RA Bouwmeester T., Acker-Palmer A.; RT "Transgenic mouse proteomics identifies new 14-3-3-associated proteins RT involved in cytoskeletal rearrangements and cell signaling."; RL Mol. Cell. Proteomics 5:2211-2227(2006). RN [10] RP INTERACTION WITH EFNB1 AND NCK2, AND TISSUE SPECIFICITY. RX PubMed=17310244; DOI=10.1038/nn1858; RA Segura I., Essmann C.L., Weinges S., Acker-Palmer A.; RT "Grb4 and GIT1 transduce ephrinB reverse signals modulating spine RT morphogenesis and synapse formation."; RL Nat. Neurosci. 10:301-310(2007). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-601, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-224, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain; RX PubMed=18034455; DOI=10.1021/pr0701254; RA Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.; RT "Large-scale identification and evolution indexing of tyrosine RT phosphorylation sites from murine brain."; RL J. Proteome Res. 7:311-318(2008). RN [13] RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION RP PHENOTYPE. RX PubMed=19273721; DOI=10.1161/circulationaha.108.823997; RA Pang J., Hoefen R., Pryhuber G.S., Wang J., Yin G., White R.J., Xu X., RA O'Dell M.R., Mohan A., Michaloski H., Massett M.P., Yan C., Berk B.C.; RT "G-protein-coupled receptor kinase interacting protein-1 is required for RT pulmonary vascular development."; RL Circulation 119:1524-1532(2009). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-554, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic fibroblast; RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200; RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.; RT "Large scale localization of protein phosphorylation by use of electron RT capture dissociation mass spectrometry."; RL Mol. Cell. Proteomics 8:904-912(2009). RN [15] RP TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=19383529; DOI=10.1016/j.neulet.2009.04.037; RA Schmalzigaug R., Rodriguiz R.M., Bonner P.E., Davidson C.E., Wetsel W.C., RA Premont R.T.; RT "Impaired fear response in mice lacking GIT1."; RL Neurosci. Lett. 458:79-83(2009). RN [16] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=20043896; DOI=10.1016/j.brainres.2009.11.084; RA Menon P., Deane R., Sagare A., Lane S.M., Zarcone T.J., O'Dell M.R., RA Yan C., Zlokovic B.V., Berk B.C.; RT "Impaired spine formation and learning in GPCR kinase 2 interacting RT protein-1 (GIT1) knockout mice."; RL Brain Res. 1317:218-226(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-368; SER-371; SER-394; RP SER-397; THR-401; SER-419; SER-422; SER-426; SER-545; THR-546; SER-570; RP SER-601; SER-605 AND THR-610, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, RC Pancreas, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [18] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=21499268; DOI=10.1038/nm.2330; RA Won H., Mah W., Kim E., Kim J.W., Hahm E.K., Kim M.H., Cho S., Kim J., RA Jang H., Cho S.C., Kim B.N., Shin M.S., Seo J., Jeong J., Choi S.Y., RA Kim D., Kang C., Kim E.; RT "GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice."; RL Nat. Med. 17:566-572(2011). RN [19] RP INTERACTION WITH GRIN3A, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=24297929; DOI=10.1073/pnas.1312211110; RA Fiuza M., Gonzalez-Gonzalez I., Perez-Otano I.; RT "GluN3A expression restricts spine maturation via inhibition of GIT1/Rac1 RT signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 110:20807-20812(2013). RN [20] RP INTERACTION WITH ENTR1. RX PubMed=23108400; DOI=10.1038/onc.2012.485; RA Hagemann N., Ackermann N., Christmann J., Brier S., Yu F., Erdmann K.S.; RT "The serologically defined colon cancer antigen-3 interacts with the RT protein tyrosine phosphatase PTPN13 and is involved in the regulation of RT cytokinesis."; RL Oncogene 32:4602-4613(2013). RN [21] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=25138700; DOI=10.1007/s11010-014-2173-5; RA Sheu T.J., Zhou W., Fan J., Zhou H., Zuscik M.J., Xie C., Yin G., RA Berk B.C.; RT "Decreased BMP2 signal in GIT1 knockout mice slows bone healing."; RL Mol. Cell. Biochem. 397:67-74(2014). RN [22] RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE. RX PubMed=24586541; DOI=10.1371/journal.pone.0089127; RA Yin G., Sheu T.J., Menon P., Pang J., Ho H.C., Shi S., Xie C., Smolock E., RA Yan C., Zuscik M.J., Berk B.C.; RT "Impaired angiogenesis during fracture healing in GPCR kinase 2 interacting RT protein-1 (GIT1) knock out mice."; RL PLoS ONE 9:e89127-e89127(2014). RN [23] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=25792865; DOI=10.5607/en.2015.24.1.8; RA Hong S.T., Mah W.; RT "A critical role of GIT1 in vertebrate and invertebrate brain RT development."; RL Exp. Neurobiol. 24:8-16(2015). RN [24] RP DISRUPTION PHENOTYPE. RX PubMed=26113791; DOI=10.5607/en.2015.24.2.126; RA Mah W.; RT "Aberrant Thalamocortical Synchrony Associated with Behavioral RT Manifestations in Git1 (-/-) Mice."; RL Exp. Neurobiol. 24:126-132(2015). RN [25] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=29554125; DOI=10.1371/journal.pone.0194350; RA Martyn A.C., Toth K., Schmalzigaug R., Hedrick N.G., Rodriguiz R.M., RA Yasuda R., Wetsel W.C., Premont R.T.; RT "GIT1 regulates synaptic structural plasticity underlying learning."; RL PLoS ONE 13:e0194350-e0194350(2018). RN [26] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=31502302; DOI=10.1111/cpr.12689; RA Li L., Tang P., Zhou Z., Wang Q., Xu T., Zhao S., Huang Y., Kong F., RA Liu W., Cheng L., Zhou Z., Zhao X., Gu C., Luo Y., Tao G., Qian D., RA Chen J., Fan J., Yin G.; RT "GIT1 regulates angiogenic factor secretion in bone marrow mesenchymal stem RT cells via NF-kappaB/Notch signalling to promote angiogenesis."; RL Cell Prolif. 52:e12689-e12689(2019). RN [27] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=32460388; DOI=10.1002/jbmr.4099; RA Zhao S.J., Liu H., Chen J., Qian D.F., Kong F.Q., Jie J., Yin G.Y., RA Li Q.Q., Fan J.; RT "Macrophage GIT1 Contributes to Bone Regeneration by Regulating RT Inflammatory Responses in an ERK/NRF2-Dependent Way."; RL J. Bone Miner. Res. 35:2015-2031(2020). RN [28] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=33010377; DOI=10.1016/j.mri.2020.09.023; RA Badea A., Schmalzigaug R., Kim W., Bonner P., Ahmed U., Johnson G.A., RA Cofer G., Foster M., Anderson R.J., Badea C., Premont R.T.; RT "Microcephaly with altered cortical layering in GIT1 deficiency revealed by RT quantitative neuroimaging."; RL Magn. Reson. Imaging 76:26-38(2021). CC -!- FUNCTION: GTPase-activating protein for ADP ribosylation factor family CC members, including ARF1. Multidomain scaffold protein that interacts CC with numerous proteins and therefore participates in many cellular CC functions, including receptor internalization, focal adhesion CC remodeling, and signaling by both G protein-coupled receptors and CC tyrosine kinase receptors (By similarity). Through PAK1 activation, CC positively regulates microtubule nucleation during interphase. Plays a CC role in the regulation of cytokinesis; for this function, may act in a CC pathway also involving ENTR1 and PTPN13 (By similarity). May promote CC cell motility both by regulating focal complex dynamics and by the CC activation of RAC1 (By similarity). May act as scaffold for MAPK1/3 CC signal transduction, recruiting MAPK1/3 to focal adhesions after EGF CC stimulation via a Src-dependent pathway, hence stimulating cell CC migration (By similarity). Plays a role in brain development and CC function (PubMed:25792865, PubMed:33010377). Involved in the regulation CC of spine density and synaptic plasticity that is required for processes CC involved in learning (PubMed:20043896, PubMed:29554125). Plays an CC important role in dendritic spine morphogenesis and synapse formation CC (PubMed:12695502). In hippocampal neurons, recruits guanine nucleotide CC exchange factors (GEFs), such as ARHGEF7/beta-PIX, to the synaptic CC membrane. These in turn locally activate RAC1, which is an essential CC step for spine morphogenesis and synapse formation (PubMed:12695502). CC May contribute to the organization of presynaptic active zones through CC oligomerization and formation of a Piccolo/PCLO-based protein network, CC which includes ARHGEF7/beta-PIX and FAK1 (By similarity). In neurons, CC through its interaction with liprin-alpha family members, may be CC required for AMPA receptor (GRIA2/3) proper targeting to the cell CC membrane (By similarity). In complex with GABA(A) receptors and CC ARHGEF7, plays a crucial role in regulating GABA(A) receptor synaptic CC stability, maintaining GPHN/gephyrin scaffolds and hence GABAergic CC inhibitory synaptic transmission, by locally coordinating RAC1 and PAK1 CC downstream effector activity, leading to F-actin stabilization (By CC similarity). May also be important for RAC1 downstream signaling CC pathway through PAK3 and regulation of neuronal inhibitory transmission CC at presynaptic input (PubMed:21499268). Required for successful bone CC regeneration during fracture healing (PubMed:25138700, PubMed:24586541, CC PubMed:32460388). The function in intramembranous ossification may, at CC least partly, exerted by macrophages in which GIT1 is a key negative CC regulator of redox homeostasis, IL1B production, and glycolysis, acting CC through the ERK1/2/NRF2/NFE2L2 axis (PubMed:32460388). May play a role CC in angiogenesis during fracture healing (PubMed:24586541, CC PubMed:31502302). In this process, may regulate activation of the CC canonical NF-kappa-B signal in bone mesenchymal stem cells by enhancing CC the interaction between NEMO and 'Lys-63'-ubiquitinated RIPK1/RIP1, CC eventually leading to enhanced production of VEGFA and others CC angiogenic factors (By similarity). Essential for VEGF signaling CC through the activation of phospholipase C-gamma and ERK1/2, hence may CC control endothelial cell proliferation and angiogenesis CC (PubMed:19273721). {ECO:0000250|UniProtKB:Q9Y2X7, CC ECO:0000250|UniProtKB:Q9Z272, ECO:0000269|PubMed:12695502, CC ECO:0000269|PubMed:19273721, ECO:0000269|PubMed:20043896, CC ECO:0000269|PubMed:21499268, ECO:0000269|PubMed:24586541, CC ECO:0000269|PubMed:25138700, ECO:0000269|PubMed:25792865, CC ECO:0000269|PubMed:29554125, ECO:0000269|PubMed:31502302, CC ECO:0000269|PubMed:32460388, ECO:0000269|PubMed:33010377}. CC -!- SUBUNIT: Forms homodimers and possibly oligomers (By similarity). May CC forms heterooligomers with GIT2 (By similarity). Interacts with G CC protein-coupled receptor kinases, including GRK2, GRK3, GRK5 and GRK6 CC (By similarity). Interacts with PPFIA1, PPFIA2 and PPFIA4 (By CC similarity). Interacts with GRIP1 and forms a ternary complex with CC PPFIA1 and GRIP1 (By similarity). Directly interacts with ARHGEF7/beta- CC PIX, forming in vitro a heptameric complex made of a GIT1 dimer and an CC ARHGEF7 trimer (By similarity). Directly interacts with PXN/paxillin; CC this interaction is enhanced in the presence of ARHGEF7 (By CC similarity). Directly interacts (via C-terminus) with TGFB1I1/Hic-5 CC (via LD motif 3) (PubMed:12153727). Directly interacts with PTK2/FAK1 CC (By similarity). May interact with PTK2B/PYK2; this interaction may be CC indirect (By similarity). Interacts with AMPA receptors GRIA2/3 (By CC similarity). Directly interacts with protein Piccolo/PCLO (By CC similarity). Forms a complex with Ephrin-B1/EFNB1 and NCK2/GRB4 (via CC SH2); this interaction is important for spine morphogenesis and synapse CC formation. Interaction with NCK2 is transient and depends upon GIT1 CC phosphorylation at Tyr-392 (PubMed:17310244). Interacts with CC GRIN3A/GluN3A (via C-terminus); this interaction competes with GIT1 CC interaction with ARHGEF7 and limits synaptic localization of GIT1 CC (PubMed:24297929). Interacts with IKBKG/NEMO in resting bone CC mesenchymal stem cells, as well as in TNF-stimulated cells; this CC interaction may increase IKBKG affinity for 'Lys-63'-linked CC polyubiquitin chains (By similarity). Interacts with GABA(A) receptors, CC including GABRB3 and GABRG2 (By similarity). Interacts with SCRIB CC (PubMed:15182672). Interacts (via N- and C-terminus) with ENTR1/SDCCAG3 CC (via N-terminus); this interaction is direct (PubMed:23108400). May CC form a tripartite complex with ENTR1 and PTPN13 (By similarity). CC Interacts with YWHAZ (PubMed:16959763). Interacts with PAK1 (By CC similarity). Interacts with PAK3 (By similarity). Directly interacts CC (via N-terminus) with gamma-tubulin (By similarity). Interacts with CC MAPK1 and MAPK3; this interaction is required for MAPK1/3 recruitment CC to focal adhesions (PubMed:15923189). {ECO:0000250|UniProtKB:Q9Y2X7, CC ECO:0000250|UniProtKB:Q9Z272, ECO:0000269|PubMed:12153727, CC ECO:0000269|PubMed:15182672, ECO:0000269|PubMed:15923189, CC ECO:0000269|PubMed:16959763, ECO:0000269|PubMed:17310244, CC ECO:0000269|PubMed:23108400, ECO:0000269|PubMed:24297929}. CC -!- INTERACTION: CC Q68FF6; Q9ES28: Arhgef7; NbExp=2; IntAct=EBI-645933, EBI-642580; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y2X7}. CC Presynapse {ECO:0000250|UniProtKB:Q9Z272}. Postsynapse CC {ECO:0000269|PubMed:24297929}. Postsynaptic density CC {ECO:0000250|UniProtKB:Q9Z272}. Cell junction, focal adhesion CC {ECO:0000269|PubMed:15923189}. Cell projection, lamellipodium CC {ECO:0000250|UniProtKB:Q9Y2X7}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome {ECO:0000250|UniProtKB:Q9Y2X7}. CC Cytoplasm, cytoskeleton, spindle pole {ECO:0000250|UniProtKB:Q9Y2X7}. CC Note=Cycles between at least 3 distinct intracellular compartments, CC including focal adhesions, cytosolic complexes, containing at least CC PXN/paxillin, ARHGEF7 and PAK1, and membrane protrusions. During cell CC migration, moves from the disassembling adhesions into the cytosol and CC towards the leading edge. In adherent cells, localizes to adhesions. CC Recruitment to adhesions may be mediated by RAC1 and active tyrosine- CC phosphorylated PXN (By similarity). May be present in both excitatory CC and inhibitory synapses. In hippocampal neurons, recruitment of GIT1 to CC synapses is regulated by ephrinB activation and ephrinB downstream CC effector GRB4/NCK2. In hippocampal neurons, partially colocalizes with CC PCLO (By similarity). Interaction with GRIN3A limits GIT1 synaptic CC localization (By similarity). Localization to the centrosome does not CC depend upon the presence of gamma-tubulin (By similarity). CC {ECO:0000250|UniProtKB:Q9Y2X7, ECO:0000250|UniProtKB:Q9Z272}. CC -!- TISSUE SPECIFICITY: Expressed in the brain (at protein level) CC (PubMed:15182672, PubMed:16959763, PubMed:17310244, PubMed:19273721, CC PubMed:19383529, PubMed:21499268, PubMed:24297929). Also expressed at CC high levels in lung and heart (PubMed:19273721). In lung, expressed in CC endothelial cells, especially in capillaries; also expressed in smooth CC muscle and epithelial cells of bronchi (at protein level) CC (PubMed:19273721). Expressed in bone marrow mesenchymal stem cells, as CC well as in osteoclasts and bone marrow-derived macrophages (at protein CC level) (PubMed:25138700, PubMed:32460388). CC {ECO:0000269|PubMed:15182672, ECO:0000269|PubMed:16959763, CC ECO:0000269|PubMed:17310244, ECO:0000269|PubMed:19273721, CC ECO:0000269|PubMed:19383529, ECO:0000269|PubMed:21499268, CC ECO:0000269|PubMed:24297929, ECO:0000269|PubMed:25138700, CC ECO:0000269|PubMed:32460388}. CC -!- DEVELOPMENTAL STAGE: In lung, up-regulated from postnatal day 3 (P3). CC Expression levels decrease after P5 and at P25, they are similar to CC those observed at P0 (PubMed:19273721). During the fracture healing CC process, expression is strongly up-regulated in the healing callus 14 CC days after the lesion and remains highly expressed at day 21 CC (PubMed:24586541). {ECO:0000269|PubMed:19273721, CC ECO:0000269|PubMed:24586541}. CC -!- PTM: Phosphorylated on tyrosine residues by PTK2/FAK1 and SRC in CC growing fibroblasts. Phosphorylation at Tyr-392 is induced by CC activation of Ephrin-B1/EFNB1 and catalyzed by SRC family kinases. It CC is required for the interaction with NCK2 and for GIT1 recruitment to CC synapses in hippocampal neurons. {ECO:0000250|UniProtKB:Q9Z272}. CC -!- DISRUPTION PHENOTYPE: Knockout mice are born at the expected Mendelian CC ratio, but have decreased survival compared to wild-type littermates, CC with about 50% of mutant mice dying postnatally. Surviving animals CC develop normally and are fertile (PubMed:19273721, PubMed:19383529, CC PubMed:21499268, PubMed:33010377). They are however 60-70% smaller than CC wild-type littermates (PubMed:21499268). A major abnormality in CC knockout mice is impaired lung development, characterized by markedly CC reduced numbers of pulmonary blood vessels and increased alveolar CC spaces (PubMed:19273721). Although knockout mice show an unaltered CC brain gross morphology and neuronal density, they display microcephaly, CC with an overall brain size about 32% smaller compared to wild-type CC controls. This phenotype may be due to smaller neuronal size, rather CC than reduced neuron number, compared to wild-type littermates CC (PubMed:20043896, PubMed:25792865, PubMed:33010377). Mutant mice CC exhibit reduced dendritic length and spine density in the hippocampus CC and the cortex, which may lead to poor adaptation to new environments CC and impaired fear response (PubMed:19383529, PubMed:20043896, CC PubMed:25792865, PubMed:29554125). This effect on the brain is not CC uniform. Multiple brain regions suffer local atrophy, including CC extensive areas of the cortex, thalamus, and hippocampus, white matter CC tracts have a reduced volume, most notably in the anterior commissure, CC but also in the cerebral peduncle, fornix, and spinal trigeminal tract. CC On the other hand, local hypertrophy is detected in the basal ganglia, CC the accumbens, caudate putamen, and amygdala, as well as in the CC cortical layer IV, and cerebellum (PubMed:33010377). The analysis of a CC genetrap mouse strain lacking GIT1 showed phenotypic traits similar to CC attention deficit-hyperactivity disorder (ADHD), including CC hyperactivity, impaired learning and memory, and enhanced theta CC rhythms. These phenotypic traits could be reversed by amphetamines and CC methylphenidate (PubMed:21499268, PubMed:26113791). Abnormal thalamic CC oscillations, cortical theta rhythms and behavioral hyperactivity were CC also normalized by ethosuximide (PubMed:26113791). The abnormal CC behaviors decreased with age (PubMed:21499268). ADHD phenotype and CC response to amphetamines were not seen in other knockout mouse models CC (PubMed:29554125). Mutant animals show altered gait (PubMed:25792865). CC They exhibit defects in motor coordination and motor learning in CC rotarod test and abnormal spatial learning and memory (PubMed:25792865, CC PubMed:29554125). Knockout mice exhibit delayed bone fracture healing CC process. They display a persistence of cartilagenous callus and CC decreased chondrocyte proliferation and apoptosis, leading to their CC accumulation in the fracture area (PubMed:25138700, PubMed:24586541). CC The healing callus exhibits reduced blood vessel volume and number, as CC well as a reduced osteoclast number (PubMed:24586541, PubMed:31502302). CC {ECO:0000269|PubMed:19273721, ECO:0000269|PubMed:19383529, CC ECO:0000269|PubMed:20043896, ECO:0000269|PubMed:21499268, CC ECO:0000269|PubMed:24586541, ECO:0000269|PubMed:25138700, CC ECO:0000269|PubMed:25792865, ECO:0000269|PubMed:26113791, CC ECO:0000269|PubMed:29554125, ECO:0000269|PubMed:31502302, CC ECO:0000269|PubMed:33010377}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AL607072; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC079870; AAH79870.1; -; mRNA. DR CCDS; CCDS25080.1; -. DR RefSeq; NP_001004144.1; NM_001004144.1. DR PDB; 6JMU; X-ray; 2.00 A; A/B=640-770. DR PDBsum; 6JMU; -. DR AlphaFoldDB; Q68FF6; -. DR SMR; Q68FF6; -. DR BioGRID; 229822; 33. DR CORUM; Q68FF6; -. DR IntAct; Q68FF6; 34. DR MINT; Q68FF6; -. DR STRING; 10090.ENSMUSP00000037210; -. DR GlyGen; Q68FF6; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q68FF6; -. DR PhosphoSitePlus; Q68FF6; -. DR SwissPalm; Q68FF6; -. DR EPD; Q68FF6; -. DR jPOST; Q68FF6; -. DR MaxQB; Q68FF6; -. DR PaxDb; 10090-ENSMUSP00000037210; -. DR PeptideAtlas; Q68FF6; -. DR ProteomicsDB; 268825; -. DR Pumba; Q68FF6; -. DR ABCD; Q68FF6; 1 sequenced antibody. DR Antibodypedia; 1365; 581 antibodies from 36 providers. DR DNASU; 216963; -. DR Ensembl; ENSMUST00000037285.10; ENSMUSP00000037210.4; ENSMUSG00000011877.14. DR GeneID; 216963; -. DR UCSC; uc007kgy.1; mouse. DR AGR; MGI:1927140; -. DR CTD; 28964; -. DR MGI; MGI:1927140; Git1. DR VEuPathDB; HostDB:ENSMUSG00000011877; -. DR eggNOG; KOG0818; Eukaryota. DR GeneTree; ENSGT00940000159604; -. DR InParanoid; Q68FF6; -. DR OMA; IDHKNGH; -. DR OrthoDB; 2877020at2759; -. DR PhylomeDB; Q68FF6; -. DR TreeFam; TF317762; -. DR Reactome; R-MMU-3928664; Ephrin signaling. DR Reactome; R-MMU-9013149; RAC1 GTPase cycle. DR Reactome; R-MMU-9013404; RAC2 GTPase cycle. DR Reactome; R-MMU-9013406; RHOQ GTPase cycle. DR Reactome; R-MMU-9013420; RHOU GTPase cycle. DR Reactome; R-MMU-9013423; RAC3 GTPase cycle. DR Reactome; R-MMU-9013424; RHOV GTPase cycle. DR BioGRID-ORCS; 216963; 2 hits in 78 CRISPR screens. DR ChiTaRS; Git1; mouse. DR PRO; PR:Q68FF6; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; Q68FF6; Protein. DR Bgee; ENSMUSG00000011877; Expressed in superior frontal gyrus and 245 other cell types or tissues. DR ExpressionAtlas; Q68FF6; baseline and differential. DR GO; GO:0044305; C:calyx of Held; IDA:SynGO. DR GO; GO:0005813; C:centrosome; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0030425; C:dendrite; ISO:MGI. DR GO; GO:0005768; C:endosome; ISO:MGI. DR GO; GO:0060076; C:excitatory synapse; ISO:MGI. DR GO; GO:0005925; C:focal adhesion; ISO:MGI. DR GO; GO:0098982; C:GABA-ergic synapse; ISO:MGI. DR GO; GO:0098978; C:glutamatergic synapse; ISO:MGI. DR GO; GO:0030426; C:growth cone; ISO:MGI. DR GO; GO:0060077; C:inhibitory synapse; ISO:MGI. DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; ISO:MGI. DR GO; GO:0097431; C:mitotic spindle pole; ISS:UniProtKB. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0098794; C:postsynapse; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell. DR GO; GO:0045202; C:synapse; IBA:GO_Central. DR GO; GO:0043015; F:gamma-tubulin binding; ISS:UniProtKB. DR GO; GO:0005096; F:GTPase activator activity; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0019903; F:protein phosphatase binding; ISO:MGI. DR GO; GO:1990782; F:protein tyrosine kinase binding; ISO:MGI. DR GO; GO:0044877; F:protein-containing complex binding; IPI:MGI. DR GO; GO:0097110; F:scaffold protein binding; ISO:MGI. DR GO; GO:0031267; F:small GTPase binding; ISO:MGI. DR GO; GO:0098879; F:structural constituent of postsynaptic specialization; ISO:MGI. DR GO; GO:0007420; P:brain development; IMP:UniProtKB. DR GO; GO:0045454; P:cell redox homeostasis; IMP:UniProtKB. DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISO:MGI. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:UniProtKB. DR GO; GO:0060996; P:dendritic spine development; ISO:MGI. DR GO; GO:0048013; P:ephrin receptor signaling pathway; IDA:MGI. DR GO; GO:0001771; P:immunological synapse formation; ISO:MGI. DR GO; GO:0001957; P:intramembranous ossification; IMP:UniProtKB. DR GO; GO:0007626; P:locomotory behavior; IMP:UniProtKB. DR GO; GO:0061743; P:motor learning; IMP:UniProtKB. DR GO; GO:0032013; P:negative regulation of ARF protein signal transduction; ISO:MGI. DR GO; GO:0045820; P:negative regulation of glycolytic process; IMP:UniProtKB. DR GO; GO:0106015; P:negative regulation of inflammatory response to wounding; IMP:UniProtKB. DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IMP:UniProtKB. DR GO; GO:0048666; P:neuron development; IMP:UniProtKB. DR GO; GO:0099645; P:neurotransmitter receptor localization to postsynaptic specialization membrane; ISO:MGI. DR GO; GO:0090063; P:positive regulation of microtubule nucleation; ISS:UniProtKB. DR GO; GO:2000646; P:positive regulation of receptor catabolic process; ISO:MGI. DR GO; GO:0099171; P:presynaptic modulation of chemical synaptic transmission; IDA:SynGO. DR GO; GO:0032012; P:regulation of ARF protein signal transduction; IBA:GO_Central. DR GO; GO:0032465; P:regulation of cytokinesis; ISO:MGI. DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; ISO:MGI. DR GO; GO:2000300; P:regulation of synaptic vesicle exocytosis; IDA:SynGO. DR GO; GO:0036465; P:synaptic vesicle recycling; IBA:GO_Central. DR CDD; cd08846; ArfGap_GIT1; 1. DR Gene3D; 1.20.5.170; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 1.10.220.150; Arf GTPase activating protein; 1. DR Gene3D; 1.20.120.330; Nucleotidyltransferases domain 2; 1. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR037278; ARFGAP/RecO. DR InterPro; IPR001164; ArfGAP_dom. DR InterPro; IPR038508; ArfGAP_dom_sf. DR InterPro; IPR047161; GIT-like. DR InterPro; IPR032352; GIT1/2_CC. DR InterPro; IPR022018; GIT1_C. DR InterPro; IPR013724; GIT_SHD. DR PANTHER; PTHR46097:SF1; ARF GTPASE-ACTIVATING PROTEIN GIT1; 1. DR PANTHER; PTHR46097; G PROTEIN-COUPLED RECEPTOR KINASE INTERACTING ARFGAP; 1. DR Pfam; PF12796; Ank_2; 1. DR Pfam; PF01412; ArfGap; 1. DR Pfam; PF12205; GIT1_C; 1. DR Pfam; PF16559; GIT_CC; 1. DR Pfam; PF08518; GIT_SHD; 2. DR PRINTS; PR00405; REVINTRACTNG. DR SMART; SM00248; ANK; 3. DR SMART; SM00105; ArfGap; 1. DR SMART; SM00555; GIT; 2. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR SUPFAM; SSF57863; ArfGap/RecO-like zinc finger; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 1. DR PROSITE; PS50115; ARFGAP; 1. DR Genevisible; Q68FF6; MM. PE 1: Evidence at protein level; KW 3D-structure; ANK repeat; Cell junction; Cell projection; Coiled coil; KW Cytoplasm; Cytoskeleton; GTPase activation; Metal-binding; Phosphoprotein; KW Reference proteome; Repeat; Synapse; Zinc; Zinc-finger. FT CHAIN 1..770 FT /note="ARF GTPase-activating protein GIT1" FT /id="PRO_0000074201" FT DOMAIN 1..124 FT /note="Arf-GAP" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00288" FT REPEAT 132..161 FT /note="ANK 1" FT REPEAT 166..195 FT /note="ANK 2" FT REPEAT 199..228 FT /note="ANK 3" FT ZN_FING 11..34 FT /note="C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00288" FT REGION 1..124 FT /note="Interaction with gamma-tubulin and localization to FT the centrosome" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT REGION 245..374 FT /note="Interaction with PCLO" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT REGION 253..424 FT /note="Interaction with PTK2/FAK1" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT REGION 254..376 FT /note="Interaction with ARHGEF7" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT REGION 363..425 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 375..596 FT /note="Interaction with NCK2 and GRIN3A" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT REGION 375..596 FT /note="Required for localization at synapses" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT REGION 420..475 FT /note="Interaction with MAPK1" FT /evidence="ECO:0000269|PubMed:15923189" FT REGION 429..629 FT /note="Interaction with IKBKG" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT REGION 578..615 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 646..770 FT /note="Interaction with PXN and TGFB1I1" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT COILED 449..483 FT /evidence="ECO:0000255" FT COMPBIAS 363..380 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 407..425 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 224 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:18034455" FT MOD_RES 368 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 371 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 373 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT MOD_RES 379 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT MOD_RES 384 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT MOD_RES 392 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT MOD_RES 394 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 397 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 401 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 419 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 422 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 426 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 507 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Y2X7" FT MOD_RES 545 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 546 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 554 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:19131326" FT MOD_RES 563 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 570 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 580 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT MOD_RES 601 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 605 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 610 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 639 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9Z272" FT MUTAGEN 420..475 FT /note="Missing: Loss of interaction with MAPK1." FT /evidence="ECO:0000269|PubMed:15923189" FT HELIX 651..673 FT /evidence="ECO:0007829|PDB:6JMU" FT HELIX 677..679 FT /evidence="ECO:0007829|PDB:6JMU" FT HELIX 680..695 FT /evidence="ECO:0007829|PDB:6JMU" FT STRAND 700..704 FT /evidence="ECO:0007829|PDB:6JMU" FT HELIX 705..726 FT /evidence="ECO:0007829|PDB:6JMU" FT HELIX 739..767 FT /evidence="ECO:0007829|PDB:6JMU" SQ SEQUENCE 770 AA; 85300 MW; C516E7A49578D0B4 CRC64; MSRKGPRAEV CADCSAPDPG WASISRGVLV CDECCSVHRS LGRHISIVKH LRHSAWPPTL LQMVHTLASN GANSIWEHSL LDPAQVQSGR RKANPQDKVH PIKSEFIRAK YQMLAFVHKL PCRDDDGVTA KDLSKQLHSS VRTGNLETCL RLLSLGAQAN FFHPEKGTTP LHVAAKAGQT LQAELLVVYG ADPGSPDVNG RTPIDYARQA GHHELAERLV ECQYELTDRL AFYLCGRKPD HKNGHYIIPQ MADRSRQKCM SQSLDLSELA KAAKKKLQAL SNRLFEELAM DVYDEVDRRE NDAVWLATQN HSTLVTERSA VPFLPVNPEY SATRNQGRQK LARFNAREFA TLIIDILSEA KRRQQGKSLS SPTDNLELSA RSQSELDDQH DYDSVASDED TDQEPLPSAG ATRNNRARSM DSSDLSDGAV TLQEYLELKK ALATSEAKVQ QLMKVNSSLS DELRRLQREI HKLQAENLQL RQPPGPVPPP SLPSERAEHT LMGPGGSTHR RDRQAFSMYE PGSALKPFGG TPGDELATRL QPFHSTELED DAIYSVHVPA GLYRIRKGVS ASSVPFTPSS PLLSCSQEGS RHASKLSRHG SGADSDYENT QSGDPLLGLE GKRFLELSKE DELHPELESL DGDLDPGLPS TEDVILKTEQ VTKNIQELLR AAQEFKHDSF VPCSEKIHLA VTEMASLFPK RPALEPVRSS LRLLNASAYR LQSECRKTVP PEPGAPVDFQ LLTQQVIQCA YDIAKAAKQL VTITTREKKQ //