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FLASH GENE
Symbol GIT1 contributors: mct/pgu - updated : 11-02-2016
HGNC name G protein-coupled receptor kinase-interactor 1
HGNC id 4272
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal ARF GTPase-activating protein (ARF-GAP) domain (AAs 1–124)
  • three ankyrin (ANK) repeats (AAs 130–254)
  • a Spa2-homology domain (SHD) (AAs 264–374), that mediates binding to the RAC1/CDC42-specific exchange factor PIX
  • a coiled-coil domain
  • a C terminus that includes paxillin-binding domain (AAs 624–770)
  • mono polymer heteromer , complex
    HOMOLOGY
    interspecies homolog to rattus Git1 (96.85 pc)
    homolog to murine Git1 (97.77 pc)
    Homologene
    FAMILY GIT protein family
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     plasma membrane,junction,adherens
        intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    text
  • observed at different subcellular locations, including focal adhesions (FAs), membrane protrusions, adherens junctions, and the centrosome
  • basic FUNCTION
  • GTPase-activating protein for the ADP ribosylation factor family
  • involved in controlling vesicle trafficking, adhesion
  • and cytoskeletal organization
  • may be acting as a scaffold protein to facilitate c-Src-dependent activation of MAP2K1-MAPK1/MAPK2 in response to both GPCRs and TKRs
  • playing a critical role in spine and synapse formation
  • regulating protrusive activity in cells by phosphorylation of serine 709 in GIT1
  • may play a role for cytoskeletal reorganization during platelet aggregation
  • play an important role in initiating the disassembly of focal adhesions
  • multidomain protein that plays an important role in cell adhesion, motility, cytoskeletal remodeling, and membrane trafficking
  • essential mediator for VEGFA-induced endothelial cells podosome formation and cell migration via PLCgamma
  • critical role for GIT1 in pulmonary vascular development by regulating VEGF-induced PLCG and ERK1/2 activation
  • with ARHGEF7 regulate HGF-induced lamellipodia formation and WASF2 transport
  • key regulator of bone mass by regulating osteoclast function
  • multi-function scaffold protein, regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation
  • plays an important role in NOS3 function, in both normal and abnormal pathophysiologic states
  • could be important in vascular signaling and disease
  • multifunctional protein that acts as a GTPase-activating protein (GAP) for Arf GTPases, as well as serves as a scaffold for a number of different signaling proteins
  • multidomain protein GIT1 is involved in cytoskeletal rearrangements and cell motility
  • is known to be important for cell spreading and migration, processes which rely on paxillin trafficking and focal adhesion turnover
  • MAT2B and GIT1 form a scaffold, which recruits and activates MEK and ERK to promote growth and tumorigenesis
  • is a novel mediator of vascular remodeling by regulating vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis through phospholipase C gamma and extracellular signal-regulated kinase 1/2 signaling pathways
  • GIT1, GIT2, ARHGEF7 and RHOJ all colocalised in focal adhesions and depended on each other for their recruitment to focal adhesions
  • GIT1 and ARHGEF7 are involved in Ag-induced chemotaxis, a possible mecanism of concerted action of tyrosine kinases, GIT1/ARHGEF7 proteins, and Ca(2+) in the propagation of signals leading to the regulation of microtubule nucleation in activated mast cells
  • distinct roles for GIT1 and GIT2 in regulating neurotransmitter release strength, with GIT1 as a specific regulator of presynaptic release probability
  • GIT1/ARHGEF7 signaling proteins with PAK1 kinase represent a novel regulatory mechanism of microtubule nucleation in interphase cells
  • GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf) small GTP-binding proteins, and function to limit the activity of Arf proteins
  • CELLULAR PROCESS cell organization/biogenesis
    cell communication
    cell migration & motility
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • signaling complex, consisting of GIT1, ARHGEF6, AKT1, and PAKs, that plays an essential role in the regulation of dendritic spine and synapse formation
  • forming a complex Scrib-ARHGEF7-GIT1
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with G protein-coupled receptor kinases : ADRBK1, PPFIA1 and PPFIA4
  • interacting with ARHGEF6
  • RAC1 and RAC3 interact with GIT1, a multifunctional Arf-GAP protein, which regulates cell-matrix adhesion, cell spreading and endocytosis
  • GIT1 and ARHGEF7 form a constitutively associated complex that acts as a scaffold to allow the formation of large multiprotein assemblies that regulate synaptogenesis, cell polarity and cell migration
  • interacts with paxillin through the LD2 and LD4 motif
  • PTK2
  • binding of GIT1 and ERK1/2 was functionally important (CC domain of ERK1/2 is necessary for binding to GIT1, for ERK1/2 activation in focal adhesions, and for cell spreading and migration)
  • substrate of PTPRZ1, with MAGI1, and GTPase-activating protein for Rho GTPase (ARHGAP35)
  • interacted with NOS3 in the endothelial cell cytoplasm, and this robust association was associated with stimulatory NOS3 phosphorylation (Ser1177), enzyme activation
  • roles for GIT1 and its interactions with the Arf GTPases and paxillin in oncogenic transformation
  • cellular activity of GIT1 via serine 46 phosphorylation is exclusively regulated by PRKD3, thus identifying GIT1 as the first specific substrate ofPRKD3
  • GRIN3A binds GIT1, a postsynaptic scaffold that assembles actin regulatory complexes, including the RAC1 guanine nucleotide exchange factor ARHGEF7, to promote RAC1 activation in spines
  • PDGFA regulates chondrocyte proliferation through activation of ERK1/2 pathway by upregulation of GIT1 expression and RAC1 phosphorylation
  • ARHGEF7 and GIT1 are required for synaptic GABA(A)R surface stability through the activity of the GTPase RAC1 and downstream effector PAK1
  • ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex
  • cell & other
    REGULATION
    Phosphorylated by regulated by protein kinase D3 (PRKD3) through direct phosphorylation on serine 46 (this phosphorylation represents a molecular switch by which GIT1 localization, paxillin trafficking, and cellular protrusive activity are regulated)
    Other regulated in a vascular endothelial liver injury model
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility to Attention deficit hyperactivity disorder (ADHD)
    Variant & Polymorphism SNP
  • intronic SNP, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility
  • Candidate gene
    Marker
  • ITGA2B, ITGA8, GIT1, and SHC1 were identified as independent prognostic factors of overall survival of clear cell renal cell carcinoma
  • Therapy target
    SystemTypeDisorderPubmed
    osteoarticularboneostéoporosis
    potential target for osteoporosis therapy
    ANIMAL & CELL MODELS
  • Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory