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FLASH GENE

Symbol

COL18A1

contributors: SGE - updated : 18-01-2018

HGNC name	collagen, type XVIII, alpha 1
HGNC id	2195

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

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 blood / hematopoietic spleen       highly Cardiovascular vessels capillary     highly Digestive liver       highly Endocrine pancreas       highly Nervous brain         Reproductive male system prostate       Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective         Epithelial secretory glandular endocrine   Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol   epithelial cell Cardiovascular endothelial cell

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, fetal

Text	neural tube, retina

PROTEIN

PHYSICAL PROPERTIES		globular
STRUCTURE

motifs/domains	thrombospondin N-terminal-like domain with a zinc-binding site (its integrity is essential
	for the stability and biological functions of endostatin)
	ten interrupted triple helical domains
	non triple helical regions with the 184 C terminal residues corresponding to endostatin

conjugated

GlycoP

mono polymer

homomer , trimer

isoforms

Precursor

precursor of endostatin (a potent antiangiogenic protein) which is proteolytically produced by the C-terminal fragment of type XVIII collagen

HOMOLOGY

interspecies	homolog to murine Col18a1 (80.3pc)
	homolog to rattus Col18a1 (79.6pc)

Homologene

FAMILY	fibril-associated collagens with interrupted helices (FACIT) family
	multiplexin collagen family

CATEGORY

adhesion , structural protein

SUBCELLULAR LOCALIZATION	extracellular
text	extracellular matrix, part of basement membrane molecular networks
	colocalized with TGM2 in the extracellular matrix secreted by endothelial cells under hypoxia, which stimulates angiogenesis

basic FUNCTION	playing an important role in retinal structure, in eye organization and in neural tube closure
	maintaining the structure of connective tissue
	inhibiting endothelial cell proliferation (G(1) arrest) by down-regulation of the cyclin D1 promoter and angiogenesis (endostatin)
	inhibiting angiogenesis by binding to the heparan sulphate proteoglycans and promoting formation of focal adhesion and actin stress fibers
	involved in growth factor signaling
	decreasing the hyperphosphorylated retinoblastoma gene product and down-regulating cyclin D1 mRNA and protein (endostatin)
	playing an essential role for RPE function, and suggest an important role of this collagen in Bruch's membrane
	endogenous inhibitor of angiogenesis, that inhibits proliferation and migration of endothelial cells
	N-terminal integrity is very critical for its stability
	and biological functions and expression systems make a huge difference with respect to the properties of endostatin
	anti-angiogenic molecules, such as CNMD and COL18A1, have pivotal roles in preserving the avascularity of cartilage
	promotes soft callus formation but inhibits callus remodeling during fracture healing most probably by an inhibition of angiogenesis
	has a specific activity, independent of baseline synapse development, that is required for the homeostatic modulation of presynaptic calcium influx and neurotransmitter release
	endogenous angiogenesis inhibitor with broad-spectrum antitumor activities
	has novel ATPase activity, which mediates its antiangiogenic and antitumor activities
	antiangiogenic factor, that is enriched in aging kidneys
	kidney fibrosis in aging may represent a natural outcome of upregulated COL18A1 and TGM2, but more likely it appears to be a result of cumulative stresses occurring on the background of synergistically acting geronic (aging) proteins, COL18A1 and TGM2

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

development

text	histogenesis and organogenesis
	negative control of cell proliferation

PATHWAY

metabolism

signaling

sensory transduction/vision

a component

INTERACTION

DNA

RNA

small molecule	metal binding,
	Zn2+ binding

protein	binding to the heparan sulphate proteoglycans
	binding to ITGA5 beta1 (to the inhibition of focal adhesion kinase MAP2K1, mitogen -activated protein kinase pathway)
	endogenous angiogenesis inhibitor which requires E-selectin for its antiangiogenic activity
	interacting with Integrin-heparan sulfate (may play a role in endostatin signaling by contributing to its localization to lipid rafts at the surface of endothelial cells) (Boniface 2009)
	interacting with receptor nucleolin
	interaction with TGM2 might participate in the concerted regulation of angiogenesis and tumorigenesis by COL18A1 and TGM2
	cysteine cathepsins S and L modulate anti-angiogenic activities of COL18A1
	interaction between COL18A1 short peptide and FLT4
	COL18A1 is an interactive partner of transglutaminase 2 (TGM2), an enzyme that cross-links extracellular matrix proteins

cell & other

REGULATION

Other

excess of the COL18A1 Tsp-1 domain is deleterious in the eye, possibly by impairing certain functions of the full-length molecule

ASSOCIATED DISORDERS

corresponding disease(s)

KNO

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in primary Sjögren syndrome, particularly in those with interstitial lung disease (ILD)

Susceptibility

to age-related macular degeneration

Variant & Polymorphism other	polymorphism at position 1437 in prostate cancer (heterozygous Asn-1437 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous Asp-1437 individuals)
	allele N104 for the endostatin domain represent a modifier allele for disorder in which angiogenesis is important, such a cancer
	SNP in COL18A1 are associated with hepatopulmonary syndrome

Candidate gene	high expression is associated with poor prognosis in patients with metastatic carcinoma
Marker	serum COL18A1 as a potential biomarker in
	Pulmonary arterial hypertension (PAH) with the capacity to predict poor outcomes
Therapy target
	System Type Disorder Pubmed cancer angiogenesis   construction of endostatin analogues with high ATPase activity may provide a new direction for the development of more potent antiangiogenic drugs neurosensorial visual   therapeutic up-regulation may be a new strategy in the treatment of neovascular AMD (age-related macular degeneration) respiratory lung   COL18A1/ES is a potential new therapeutic target in Pulmonary arterial hypertension (PAH) miscelleaneous hypertension   coadministration of COL18A1 with VEGFA inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression

ANIMAL & CELL MODELS

	Collagen XVIII deficiency leads to anterior and posterior eye defects in Col18a1(-/-) mice
	Col18a1(-/-) mice showed effacement of the glomerular podocyte foot processes, and microindentation studies showed changes in the mechanical properties of the glomeruli