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FLASH GENE

Symbol

FLT1

contributors: mct - updated : 21-09-2016

HGNC name	fms-related tyrosine kinase 1 (vascular endothelial growth factor/vascular permeability factor receptor)
HGNC id	3763

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

text	splice variant SFLT1 (soluble) with high affinity for VEGF

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002019 30 splicing 7123 NP_002010 150.77 1338 - 1990 2158038 also called FLT1 type I membrane protein NM_001159920 13 splicing 6499 NP_001153392 - 687 . placenta highly . serum 2011 21168388 also called sFLT1 playing an inhibitory role in angiogenesis soluble protein heterodimerizing with FLK1 six N terminal immunoglobulin-like domains inhibiting mitogenic activity of vascular endothelial cell growth factor in hypoxia, endothelial cells displayed nearly a 10-fold increase levels in comparison to normoxia conditions NM_001160031 12 - 1911 NP_001153503 - 541 - 2011 21168388 NM_001160030 15 - 2968 NP_001153502 - 733 - 2011 21168388

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 Endocrine parathyroid       highly   thyroid       highly Nervous nerve       highly   nerve cranial nerve     highly Reproductive female system placenta     predominantly Respiratory lung       lowly Urinary kidney       moderately Visual eye anterior segment cornea   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     moderately Connective adipose     highly Epithelial barrier lining retinal pigment epithelium (RPE)   highly

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic monocyte Blood/Hematopoietic platelet Cardiovascular endothelial cell Urinary podocyte Homo sapiens

cell lineage
cell lines	CLL B cell lines
fluid/secretion	plasma, serum, blood

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	extracellular segment with seven immunoglobulin-like C2-type domains
	a unique transmembrane segment TM1
	a short intracellular juxtamembrane region
	a split tyrosine-kinase domain
	a C terminal sequence

conjugated

GlycoP

HOMOLOGY

interspecies	homolog to rattus Flt1 (82.47 pc)
	homolog to murine Flt1 (82.04 pc)

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	Fms family of receptor tyrosine kinase
	CSF-1/PDGF receptor subfamily

CATEGORY

enzyme , receptor membrane tyrosine kinase

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus
text	a membrane type I protein isoform and a soluble isoform
	primarily localized in the nucleus of endothelial cells (
	is primarily located at the basal aspect of podocyte foot processes, adjacent to the slit diaphragm and in endosomes
	ROBO4 partially colocalizes with FLT1 in endocytic vesicles, whereas SCARB1 shows more extensive colocalization with FLT1 on the surface of podocytes

basic FUNCTION	inhibitor of VDGF dependent PI3-kinase activation and endothelial cell migration through the juxtamembrane domain
	functioning as an antagonist of vascular endothelial growth factor
	playing an essential role in embryonic vasculature, and for preserving the avascular ambit of the cornea
	acts to promote endothelial tubule branching in an organotypic model of angiogenesis via a mechanism that requires RAB4A and alphavbeta3 Integrin (
	FLT1 signaling is required for endothelial-cell survival, while KDR regulates capillary tube formation )
	contribute to vessel maturation by mediating a dialogue between endothelial cells (ECs) and mural cells that leads to blood vessel stabilization
	axis KDR/FLT1 is implicated in endochondral bone repair
	in primary endothelial cells, hypoxia stimulates VEGFA and FLT1 expression but decreases KDR levels
	regulates the VEGF-triggered migration of endothelial cells and macrophages
	having functions in malignant melanoma-initiating cells that regulates vasculogenic mimicry and associated laminin production, and promote tumor growth
	regulates the VEGFA-triggered migration of endothelial cells and macrophages
	autocrine function for sFLT1 to control pericyte behavior
	promotes attachment and reorganization of the actin cytoskeleton of podocytes
	VEGFA-induced sFLT1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis
	sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGFA, suggesting that a local increase in VEGFA can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications
	secreted FLT1 and cleaved FLT1 will tend to have local effects as a VEGFA antagonist when released from cells expressing KDR and more distant effects when released from cells lacking KDR
	cell cycle regulator CCNA1 in association with FLT1, is required for haematopoietic stem/progenitor cells (HSPC) and their niches to maintain their function and proper interaction
	appears to play a role in oxidative stress, which promotes apoptosis of trophoblasts and may be an important mechanism in the development of Pre-eclampsia (PE)
	soluble FLT1, plays a central role in preeclamptic pathophysiology 5)

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

text	positive control of cell proliferation

PATHWAY

metabolism

signaling

non-canonical WNT–FLT1 pathway involved in regulation of angiogenesis in myeloid cells

a component

FLT1 subunits modulate VEGFA activity predominantly by forming heterodimer receptors with KDR subunits and such heterodimers regulate endothelial cell homeostasis

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	binding to VEGF, VEGFB, PGF and FLK1
	NFAT target gene in endothelial cells
	GNB2L1 (receptor for activated protein kinase C 1) binds to FLT1, and regulates FLT1-mediated cell migration via activation of a PI3K/Akt pathway
	JMJD6 mediates splicing of FLT1 by interacting with U2AF2
	VEGFB is a high-affinity FLT1 ligand that, unlike PGF, cannot efficiently induce signaling downstream of FLT1
	stimulates likely angiogenesis via transactivation of the EGF receptor, which promotes the phosphorylation of FLT1 and activation of SYK independent of VEGFA expression
	FLT1 is involved in regulating phosphorylation of nephrin (
	LGALSs vascular permeability through the NRP1/FLT1 complex
	JMJD6 may play a role in regulating the production of FLT1 in the preeclamptic placenta
	EPO had enhanced carcinogenesis through increase of EPOR and FLT1 expression, and thereby contributed to tumor development

cell & other

REGULATION

activated by

hypoxia, in primary endothelial cells

induced by

vitronectin

repressed by

fibrin

Other

regulated by PAX3 or PAX3-FOXO1A

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in hemangioma endothelial cells, resulting in VEGF-dependent activation of KDR and downstream signaling pathways constitutional     --over   in placentas of preeclampsia and HELLP syndrome constitutional     --over   higher expression in severe preeclampsia or eclampsia than in normal pregnancy constitutional     --over   in coronary artery disease where cardiac tissue has been subjected to prolonged or chronic hypoxia, increased VEGFR1, thus selecting for non-ischemic in endothelial cells in promoting pro-angiogenic responses including nitric oxide production constitutional     --low   loss of expression of FLT1, moderate expression of KDR and high concentration of nitrate associated with aneurysm formation constitutional     --over   concentration of FLT1 in severe preeclampsia is higher compared with normal pregnancy constitutional     --over   contributes to endothelial injury in in IgA nephropathy (IgAN) constitutional     --low   decreased expression of FLT1 in decidua and weaker VEGFA and KDR expression in placental villi and decidua may be associated with early pregnancy loss constitutional     --low   decreased significantly in serum of patients with ALS

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	with PLGF, is an effective biomarker in predicting PE (preeclampsia) during the second trimester, before the clinical onset of PE
	sFLT1 levels may be an effective biomarker to predict the progression of heart failure in patients with coronary artery disease (CAD)
	elevated levels of FLT1 are associated with adverse outcomes in stable patients with heart failure
	FLT1 mRNA expression in maternal blood can be used as a marker to predict the development of fetal growth restriction (FGR), long before a clinical diagnosis is made
	molecular detection of MAML2 rearrangement combined with FLT1 may be of important clinical value for Primary pulmonary mucoepidermoid carcinoma (PMEC)
Therapy target	in treating neovascular diseases
	System Type Disorder Pubmed cardiovascular aquired   potential therapy target in conditions where inducing angiogenesis might be benficial (preeclampsia, wound healing, strocke and heart disease) cancer     therapeutic potential for FLT1-modifying drugs in cancer pain cancer angiogenesis   disrupting PGF/FLT1 pathway could modulate endothelial-colony-forming cells (ECFCs)-induced tubulogenesis, the cell type responsible for newly formed vessels

ANIMAL & CELL MODELS

	Flk1 disrupted transgenic mice
	mdx:Flt-1(+/-) adult mice display a developmentally increased vascular density in skeletal muscle compared with the wild-type and mdx mice (mdx:utrophin(-/-):Flt-1(+/-) mice display improved muscle histology and significantly higher survival rates compared with the mdx:utrophin(-/-) mice, which show more severe muscle phenotypes than the mdx mice)
	loss of normal foot process structure in mice lacking Flt1 results in massive protein leakage into the urine due to disruption of the glomerular permeability barrier, resulting eventually in kidney failure