Protein: ARF GTPase-activating protein GIT1 (ARF GAP GIT1) (Cool-associated and tyrosine-phosphorylated protein 1) (CAT-1) (CAT1) (G protein-coupled receptor kinase-interactor 1) (GRK-interacting protein 1) (p95-APP1) (Q9Y2X7)
Organism: Homo sapiens (Human)
Function: GTPase-activating protein for ADP ribosylation factor family members, including ARF1. Multidomain scaffold protein that interacts with numerous proteins and therefore participates in many cellular functions, including receptor internalization, focal adhesion remodeling, and signaling by both G protein-coupled receptors and tyrosine kinase receptors (By similarity). Through PAK1 activation, positively regulates microtubule nucleation during interphase. Plays a role in the regulation of cytokinesis; for this function, may act in a pathway also involving ENTR1 and PTPN13. May promote cell motility both by regulating focal complex dynamics and by local activation of RAC1. May act as scaffold for MAPK1/3 signal transduction in focal adhesions. Recruits MAPK1/3/ERK1/2 to focal adhesions after EGF stimulation via a Src-dependent pathway, hence stimulating cell migration. Plays a role in brain development and function. Involved in the regulation of spine density and synaptic plasticity that is required for processes involved in learning (By similarity). Plays an important role in dendritic spine morphogenesis and synapse formation. In hippocampal neurons, recruits guanine nucleotide exchange factors (GEFs), such as ARHGEF7/beta-PIX, to the synaptic membrane. These in turn locally activate RAC1, which is an essential step for spine morphogenesis and synapse formation. May contribute to the organization of presynaptic active zones through oligomerization and formation of a Piccolo/PCLO-based protein network, which includes ARHGEF7/beta-PIX and FAK1 (By similarity). In neurons, through its interaction with liprin-alpha family members, may be required for AMPA receptor (GRIA2/3) proper targeting to the cell membrane (By similarity). In complex with GABA(A) receptors and ARHGEF7, plays a crucial role in regulating GABA(A) receptor synaptic stability, maintaining GPHN/gephyrin scaffolds and hence GABAergic inhibitory synaptic transmission, by locally coordinating RAC1 and PAK1 downstream effector activity, leading to F-actin stabilization. May also be important for RAC1 downstream signaling pathway through PAK3 and regulation of neuronal inhibitory transmission at presynaptic input (By similarity). Required for successful bone regeneration during fracture healing (By similarity). The function in intramembranous ossification may, at least partly, exerted by macrophages in which GIT1 is a key negative regulator of redox homeostasis, IL1B production, and glycolysis, acting through the ERK1/2/NRF2/NFE2L2 axis (By similarity). May play a role in angiogenesis during fracture healing (By similarity). In this process, may regulate activation of the canonical NF-kappa-B signal in bone mesenchymal stem cells by enhancing the interaction between NEMO and 'Lys-63'-ubiquitinated RIPK1/RIP1, eventually leading to enhanced production of VEGFA and others angiogenic factors. Essential for VEGF signaling through the activation of phospholipase C-gamma and ERK1/2, hence may control endothelial cell proliferation and angiogenesis.
Subcellular location: Cytoplasm {ECO:0000269|PubMed:11896197}. Synapse {ECO:0000269|PubMed:12695502}. Presynapse {ECO:0000250|UniProtKB:Q9Z272}. Postsynapse {ECO:0000250|UniProtKB:Q9Z272}. Postsynaptic density {ECO:0000250|UniProtKB:Q9Z272}. Cell junction, focal adhesion {ECO:0000269|PubMed:10938112, ECO:0000269|PubMed:11896197, ECO:0000269|PubMed:15923189}. Cell projection, lamellipodium {ECO:0000269|PubMed:11896197}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:23108400, ECO:0000269|PubMed:27012601}. Cytoplasm, cytoskeleton, spindle pole {ECO:0000269|PubMed:27012601}. Note=Cycles between at least 3 distinct intracellular compartments, including focal adhesions, cytosolic complexes, containing at least PXN/paxillin, ARHGEF7 and PAK1, and membrane protrusions. During cell migration, moves from the disassembling adhesions into the cytosol and towards the leading edge. In adherent cells, localizes to adhesions. Recruitment to adhesions may be mediated by RAC and active tyrosine-phosphorylated PXN (PubMed:11896197). May be present in both excitatory and inhibitory synapses. In hippocampal neurons, recruitment of GIT1 to synapses is regulated by ephrinB activation and ephrinB downstream effector GRB4/NCK2. In hippocampal neurons, partially colocalizes with PCLO (By similarity). Interaction with GRIN3A limits GIT1 synaptic localization (By similarity). Localization to the centrosome does not depend upon the presence of gamma-tubulin (PubMed:27012601). {ECO:0000250|UniProtKB:Q9Z272, ECO:0000269|PubMed:11896197, ECO:0000269|PubMed:27012601}.
Sequence: MSRKGPRAEVCADCSAPDPGWASISRGVLVCDECCSVHRSLGRHISIVKHLRHSAWPPTLLQMVHTLASNGANSIWEHSLLDPAQVQSGRRKANPQDKVHPIKSEFIRAKYQMLAFVHKLPCRDDDGVTAKDLSKQLHSSVRTGNLETCLRLLSLGAQANFFHPEKGTTPLHVAAKAGQTLQAELLVVYGADPGSPDVNGRTPIDYARQAGHHELAERLVECQYELTDRLAFYLCGRKPDHKNGHYIIPQMADSLDLSELAKAAKKKLQALSNRLFEELAMDVYDEVDRRENDAVWLATQNHSTLVTERSAVPFLPVNPEYSATRNQGRQKLARFNAREFATLIIDILSEAKRRQQGKSLSSPTDNLELSLRSQSDLDDQHDYDSVASDEDTDQEPLRSTGATRSNRARSMDSSDLSDGAVTLQEYLELKKALATSEAKVQQLMKVNSSLSDELRRLQREIHKLQAENLQLRQPPGPVPTPPLPSERAEHTPMAPGGSTHRRDRQAFSMYEPGSALKPFGGPPGDELTTRLQPFHSTELEDDAIYSVHVPAGLYRIRKGVSASAVPFTPSSPLLSCSQEGSRHTSKLSRHGSGADSDYENTQSGDPLLGLEGKRFLELGKEEDFHPELESLDGDLDPGLPSTEDVILKTEQVTKNIQELLRAAQEFKHDSFVPCSEKIHLAVTEMASLFPKRPALEPVRSSLRLLNASAYRLQSECRKTVPPEPGAPVDFQLLTQQVIQCAYDIAKAAKQLVTITTREKKQ
InterPro domains: - IPR022018: ARF GTPase-activating protein GIT1, C-terminal (domain) [643-755]
- IPR036770: Ankyrin repeat-containing domain superfamily (homologous_superfamily) [44-308]
- IPR001164: Arf GTPase activating protein (domain) [1-124]
- IPR037278: ARFGAP/RecO-like zinc finger (homologous_superfamily) [5-120]
- IPR047161: ARF GTPase-activating protein Git-like (family) [1-757]
- IPR002110: Ankyrin repeat (repeat) [132-228]
- IPR013724: GIT, Spa2 homology (SHD) domain (domain) [264-358]
- IPR032352: Arf GTPase-activating protein GIT1/2, coiled-coil domain (domain) [409-473]
- IPR038508: ArfGAP domain superfamily (homologous_superfamily) [2-121]
Interaction partners: - Rho guanine nucleotide exchange factor 6
- Paxillin
- Rho guanine nucleotide exchange factor 7
- G protein-coupled receptor kinase 6
- G protein-coupled receptor kinase 4
- G protein-coupled receptor kinase 5
- Beta-adrenergic receptor kinase 1
- Protein scribble homolog
- ARF GTPase-activating protein GIT2
- Serine/threonine-protein kinase PAK 1
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0005515 (protein binding)
Biological Process (BP): GO:0008150 (biological process), GO:0051179 (localization), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0002376 (immune system process), GO:0023052 (signaling), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0048869 (cellular developmental process), GO:0051641 (cellular localization), GO:0048856 (anatomical structure development), GO:0023057 (negative regulation of signaling), GO:0048870 (cell motility), GO:0051051 (negative regulation of transport), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0002684 (positive regulation of immune system process), GO:0051234 (establishment of localization), GO:0002682 (regulation of immune system process), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0002683 (negative regulation of immune system process), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0009893 (positive regulation of metabolic process), GO:0040013 (negative regulation of locomotion), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0048523 (negative regulation of cellular process), GO:0048585 (negative regulation of response to stimulus), GO:0007154 (cell communication), GO:0007165 (signal transduction), GO:0040012 (regulation of locomotion), GO:0048522 (positive regulation of cellular process), GO:0009967 (positive regulation of signal transduction), GO:0009968 (negative regulation of signal transduction), GO:0010648 (negative regulation of cell communication), GO:0051049 (regulation of transport), GO:2000145 (regulation of cell motility), GO:0002685 (regulation of leukocyte migration), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0030154 (cell differentiation), GO:0048468 (cell development), GO:0080134 (regulation of response to stress), GO:0002686 (negative regulation of leukocyte migration), GO:0009966 (regulation of signal transduction), GO:0030155 (regulation of cell adhesion), GO:0060255 (regulation of macromolecule metabolic process), GO:0032101 (regulation of response to external stimulus), GO:0060627 (regulation of vesicle-mediated transport), GO:0002694 (regulation of leukocyte activation), GO:0045785 (positive regulation of cell adhesion), GO:0001817 (regulation of cytokine production), GO:0051048 (negative regulation of secretion), GO:0031348 (negative regulation of defense response), GO:0002831 (regulation of response to biotic stimulus), GO:0050776 (regulation of immune response), GO:0007162 (negative regulation of cell adhesion), GO:0010646 (regulation of cell communication), GO:0002697 (regulation of immune effector process), GO:0002833 (positive regulation of response to biotic stimulus), GO:0007186 (G protein-coupled receptor signaling pathway), GO:0006810 (transport), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0050778 (positive regulation of immune response), GO:0007166 (cell surface receptor signaling pathway), GO:0002698 (negative regulation of immune effector process), GO:0031349 (positive regulation of defense response), GO:0080090 (regulation of primary metabolic process), GO:0002832 (negative regulation of response to biotic stimulus), GO:0050865 (regulation of cell activation), GO:1903531 (negative regulation of secretion by cell), GO:0016477 (cell migration), GO:2000146 (negative regulation of cell motility), GO:0032102 (negative regulation of response to external stimulus), GO:0031347 (regulation of defense response), GO:0030097 (hemopoiesis), GO:0007229 (integrin-mediated signaling pathway), GO:0050728 (negative regulation of inflammatory response), GO:0045089 (positive regulation of innate immune response), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:0045088 (regulation of innate immune response), GO:0051246 (regulation of protein metabolic process), GO:0022407 (regulation of cell-cell adhesion), GO:0062207 (regulation of pattern recognition receptor signaling pathway), GO:0030334 (regulation of cell migration), GO:0070663 (regulation of leukocyte proliferation), GO:0051250 (negative regulation of lymphocyte activation), GO:0030336 (negative regulation of cell migration), GO:0036211 (protein modification process), GO:0050764 (regulation of phagocytosis), GO:0050688 (regulation of defense response to virus), GO:0051247 (positive regulation of protein metabolic process), GO:0016192 (vesicle-mediated transport), GO:0071675 (regulation of mononuclear cell migration), GO:0022408 (negative regulation of cell-cell adhesion), GO:0010629 (negative regulation of gene expression), GO:0002819 (regulation of adaptive immune response), GO:0051249 (regulation of lymphocyte activation), GO:0050670 (regulation of lymphocyte proliferation), GO:0038093 (Fc receptor signaling pathway), GO:0006909 (phagocytosis), GO:0050863 (regulation of T cell activation), GO:0032944 (regulation of mononuclear cell proliferation), GO:0031399 (regulation of protein modification process), GO:2000401 (regulation of lymphocyte migration), GO:0032945 (negative regulation of mononuclear cell proliferation), GO:2000403 (positive regulation of lymphocyte migration), GO:0032946 (positive regulation of mononuclear cell proliferation), GO:0050672 (negative regulation of lymphocyte proliferation), GO:1903037 (regulation of leukocyte cell-cell adhesion), GO:1903038 (negative regulation of leukocyte cell-cell adhesion), GO:0050868 (negative regulation of T cell activation), GO:0031401 (positive regulation of protein modification process), GO:0032432 (actin filament bundle), GO:1903322 (positive regulation of protein modification by small protein conjugation or removal), GO:2000404 (regulation of T cell migration), GO:1903320 (regulation of protein modification by small protein conjugation or removal), GO:0002230 (positive regulation of defense response to virus by host), GO:0031396 (regulation of protein ubiquitination), GO:0031398 (positive regulation of protein ubiquitination)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005829 (cytosol), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0030054 (cell junction), GO:0043229 (intracellular organelle), GO:0070161 (anchoring junction), GO:0005739 (mitochondrion), GO:0043227 (membrane-bounded organelle), GO:0030055 (cell-substrate junction), GO:0043231 (intracellular membrane-bounded organelle), GO:0005925 (focal adhesion)