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FLASH GENE

Symbol

KRIT1

contributors: mct/npt - updated : 28-05-2015

HGNC name	KRIT1, ankyrin repeat containing
HGNC id	1573

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

text	several alternative transcripts differing by their 5' end, the larger lacking exon 2, the shorter skipping over exons 2, 3, 4

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_194456 20 - 4762 NP_919438 84 736 - 2001 11161805 variant 1, isoform 1 NM_004912 19 splicing 4870 NP_004903 84 736 - 2001 11161805 variant 2, isoform 1 NM_194454 19 splicing 4523 NP_919436 84 736 - 2001 11161805 variant 3, isoform 1 NM_194455 19 splicing 4997 NP_919437 84 736 - 2001 11161805 variant 4, isoform 1 NM_001013406 17 - 4231 NP_001013424 - 688 restricted 2001 11161805 variant 5, isoform 2 lacking exon 15

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       lowly   vessels         Nervous brain       lowly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Lymphoid/Immune B cell Nervous astrocyte

cell lineage
cell lines	ovary tumor cell lines
fluid/secretion

at STAGE

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