GIT1_MOUSE
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 03-AUG-2022, entry version 172.
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, Pancreas,
RC 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}.
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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; 31.
DR CORUM; Q68FF6; -.
DR IntAct; Q68FF6; 34.
DR MINT; Q68FF6; -.
DR STRING; 10090.ENSMUSP00000037210; -.
DR iPTMnet; Q68FF6; -.
DR PhosphoSitePlus; Q68FF6; -.
DR SwissPalm; Q68FF6; -.
DR EPD; Q68FF6; -.
DR jPOST; Q68FF6; -.
DR MaxQB; Q68FF6; -.
DR PaxDb; Q68FF6; -.
DR PeptideAtlas; Q68FF6; -.
DR PRIDE; Q68FF6; -.
DR ProteomicsDB; 268825; -.
DR ABCD; Q68FF6; 1 sequenced antibody.
DR Antibodypedia; 1365; 497 antibodies from 36 providers.
DR DNASU; 216963; -.
DR Ensembl; ENSMUST00000037285; ENSMUSP00000037210; ENSMUSG00000011877.
DR GeneID; 216963; -.
DR UCSC; uc007kgy.1; mouse.
DR CTD; 28964; -.
DR MGI; MGI:1927140; Git1.
DR VEuPathDB; HostDB:ENSMUSG00000011877; -.
DR eggNOG; KOG0818; Eukaryota.
DR GeneTree; ENSGT00940000159604; -.
DR InParanoid; Q68FF6; -.
DR OMA; FRNANDC; -.
DR OrthoDB; 349344at2759; -.
DR PhylomeDB; Q68FF6; -.
DR TreeFam; TF317762; -.
DR Reactome; R-MMU-3928664; Ephrin signaling.
DR Reactome; R-MMU-9013148; CDC42 GTPase cycle.
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-9013409; RHOJ 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 73 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 241 other tissues.
DR ExpressionAtlas; Q68FF6; baseline and differential.
DR Genevisible; Q68FF6; MM.
DR GO; GO:0044305; C:calyx of Held; IMP:SynGO.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005768; C:endosome; 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: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; ISO:MGI.
DR GO; GO:0098794; C:postsynapse; IDA:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; ISO:MGI.
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:0044877; F:protein-containing complex binding; IPI: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; IMP: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; IMP:SynGO.
DR GO; GO:0036465; P:synaptic vesicle recycling; IBA:GO_Central.
DR Gene3D; 1.10.220.150; -; 1.
DR Gene3D; 1.25.40.20; -; 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; IPR032352; GIT1/2_CC.
DR InterPro; IPR022018; GIT1_C.
DR InterPro; IPR013724; GIT_SHD.
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; SSF48403; 1.
DR SUPFAM; SSF57863; SSF57863; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 1.
DR PROSITE; PS50115; ARFGAP; 1.
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
