Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol KRIT1 contributors: mct/npt - updated : 28-05-2015
HGNC name KRIT1, ankyrin repeat containing
HGNC id 1573
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a N-terminal NPXY motif, and ICAP1A interacting region, a N-terminal Nudix domain, in a region previously designated as unstructured
  • a FERM (EPB41, ezrin, radixin, moesin) domain, and biological function of KRIT1 requires that its FERM domain physically interact with both the small GTPase RAP1A and the cytoplasmic tail of the Heart of glass (HEG1) membrane anchor
  • four C terminal ankyrin repeats
    • HOMOLOGY
    interspecies ortholog to murine Krit1
    Homologene
    FAMILY
  • ankyrin repeat family
  • CCM (cerebral cavernous malformation) family of proteins
    • CATEGORY tumor suppressor , signaling
    SUBCELLULAR LOCALIZATION     plasma membrane,junction,adherens
        intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule
    intracellular,nucleus
    text
  • microtubule -associated protein
  • nuclear-cytoplasmic shuttling
  • can be associated to microtubules, membranes, and adherens junctions, but also the nucleus
    • basic FUNCTION
  • microtubule associated protein, helping determine endothelial cell, and function in response to cell-cell and cell-matrix interaction by guiding cytoskeletal structure
  • may be serving as a bridging protein linking the actin cytoskeleton and integral membrane protein via adaptors
  • with ITGB1BP1, act concordantly to play a critical role in beta1-integrin-mediated cell proliferation (Zhang 2008)
  • both KRIT1 and ITGB1BP1 stabilizes and shuttles ITGB1BP1 and thus modulates its regulation of beta1-integrin-mediated signal transduction
  • represents an antiangiogenic protein to keep the endothelium quiescent and inhibits endothelial proliferation, apoptosis, migration, lumen formation, and sprouting angiogenesis in primary endothelial cell
  • strongly induces DLL4-NOTCH signaling, which promotes AKT phosphorylation but reduces phosphorylation of the mitogen-activated protein kinase ERK
  • role of CCM1 as an activator of vascular DELTA-NOTCH signaling
  • leads to potent reduction of ERK-mediated cell proliferation but to an increase of AKT-driven endothelial survival via NOTCH signaling
  • can participate in a protein complex also containing PDCD10 and CCM2
  • integral role for KRIT1 in microvessel homeostasis and the vascular response to inflammation
  • plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage
  • is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent ROS-induced cellular dysfunctions, including a reduced ability to maintain a quiescent state
  • role for KRIT1 inside the nucleus
  • KRIT1, PDCD10, and CCM2 are critical regulators of endothelial cell-cell contact and vascular homeostasis
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    GTPase signaling pathways, may be involved in the bidirectional signaling between integrin molecules and the cytoskeleton
    a component
  • ternary complex CCM1/CCM2/MAP3K3
  • HEG1-KRIT1 protein signaling as a crucial regulator of heart and vessel formation and integrity
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • KREV1 (RAP1A1) (form missing the N-terminus)
  • competing with integrin beta 1 for ICAP1A interaction through the NPXY N terminal motif of CCM1
  • interacting with CCM2
  • binds to RAP1A, a guanosine triphosphatase that maintains the integrity of endothelial junctions (Glading 2007)
  • physical interaction of KRIT1 and CCM2 proteins is required for endothelial cell-cell junctional localization, and lack of either protein destabilizes barrier function by sustaining activity of RHOA and its effector Rho kinase (ROCK)
  • KRIT1-CCM2 interaction regulates vascular barrier function by suppressing RHO/ROCK1 signaling and that this pathway is dysregulated in human CCM endothelium
  • ITG1BP1 recruits KRIT1 to the cell membrane and activates KRIT1 by changing its conformation
  • influenza virus Nd1-L may contribute to the regulation of KRIT1 nucleocytoplasmic shuttling and cooperate with KRIT1 in modulating the expression levels of the antioxidant protein SOD2
  • functions as a switch for beta1 integrin activation by antagonizing ITGB1BP1-mediated modulation of "inside-out" activation
  • KRIT1 releases ITGB1BP1 suppression of integrin activation by sequestering ITGB1BP1 away from integrin cytoplasmic tails
  • HEG1 binds in a hydrophobic pocket at the KRIT1 F1 and F3 interface, and there is no overlap with the RAP1A-binding site
  • KRIT1-ITGB1BP1 complex controls beta1 integrin-dependent endothelial contractility and fibronectin remodeling
  • KRIT1 loss of function causes a ROS-dependent upregulation of JUN
  • direct interaction between SNX17 and KRIT1 and classify KRIT1 as a SNX17 binding partner
  • KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGFA) signaling
  • interaction of KRIT1 and CCM2 and the CCM2 phosphotyrosine binding (PTB) domain displays a preference toward the third of the three KRIT1 NPX(Y/F) motifs
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) CCM1 , DEL7Q21
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS