Reviewed, UniProtKB/Swiss-Prot Q9BY76 (ANGL4_HUMAN)

Names and origin

Protein names

Recommended name:
    Angiopoietin-related protein 4
Alternative name(s):
    Angiopoietin-like 4
    Hepatic fibrinogen/angiopoietin-related protein
      Short name=HFARP

Gene names

Name:	ANGPTL4
Synonyms:	ARP4, HFARP, PGAR
ORF Names:	PP1158, PSEC0166, UNQ171/PRO197

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	406 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Protein with hypoxia-induced expression in endothelial cells. May act as a regulator of angiogenesis and modulate tumorgenesis. Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage. May exert a protective function on endothelial cells through an endocrine action. It is directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. In response to hypoxia, the unprocessed form of the protein accumulates in the subendothelial extracellular matrix (ECM). The matrix-associated and immobilized unprocessed form limits the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibits their adhesion. It also decreases motility of endothelial cells and inhibits the sprouting and tube formation By similarity.
Subunit structure	Homooligomer. The homooligomer undergoes proteolytic processing to release its carboxyl fibrinogen-like domain, which circulates as a monomer. The homooligomer unprocessed form is able to interact with the extracellular matrix By similarity.
Subcellular location	Secreted. Secreted › extracellular space › extracellular matrixBy similarity. Note= The unprocessed form interacts with the extracellular matrix. This may constitute a dynamic reservoir, a regulatory mechanism of the bioavailability of ANGPTL4 By similarity.
Tissue specificity	Expressed at high levels in the placenta, heart, liver, muscle, pancreas and lung but expressed poorly in the brain and kidney.
Post-translational modification	N-glycosylated.
Involvement in disease	Found to be highly expressed in the early stages of collagen-induced arthritis (CIA). Serum levels of ANGPTL4 are significantly lower in patients with diabetes type 2 than those in healthy subjects, suggesting that decreased ANGPTL4 could be a causative factor of this disease. Produced in ischemic tissues in conditions such as critical leg ischemia. In tumors, ANGPTL4 could be produced in the hypoxic areas surrounding necrotic regions. High levels could be produced in tumor cells of conventional renal cell carcinoma. This molecule therefore seems to be a marker of conventional renal cell carcinoma.
Sequence similarities	Contains 1 fibrinogen C-terminal domain.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Polymorphism
Domain	Coiled coil Signal
Molecular function	Developmental protein
PTM	Glycoprotein
Gene Ontology (GO)
Biological process	negative regulation of apoptosis Ref.1 Inferred from direct assay. Source: UniProtKB negative regulation of lipoprotein lipase activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of angiogenesis Ref.3 Traceable author statement. Source: UniProtKB response to hypoxia Ref.10 Non-traceable author statement. Source: UniProtKB
Cellular component	cytoplasm Inferred from direct assay. Source: HPA extracellular region Ref.1 Inferred from direct assay. Source: UniProtKB nucleus Inferred from direct assay. Source: HPA
Molecular function	enzyme inhibitor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 25	25	Potential
	Chain	26 – 406	381	Angiopoietin-related protein 4		PRO_0000009124
Regions
	Domain	179 – 401	223	Fibrinogen C-terminal
	Coiled coil	100 – 143	44	Potential
Amino acid modifications
	Glycosylation	177	1	N-linked (GlcNAc...) Potential
	Disulfide bond	188 ↔ 216		By similarity
	Disulfide bond	341 ↔ 354		By similarity
Natural variations
	Natural variant	5	1	P → L		VAR_032642
	Natural variant	40	1	E → K Associated with lower plasma levels of triglyceride and higher levels of HDL cholesterol.		VAR_032643
	Natural variant	41	1	M → I		VAR_032644
	Natural variant	67	1	S → R		VAR_032645
	Natural variant	72	1	R → L		VAR_032646
	Natural variant	77	1	G → R		VAR_032647
	Natural variant	167	1	E → K		VAR_032648
	Natural variant	174	1	P → S		VAR_032649
	Natural variant	190	1	E → Q		VAR_032650
	Natural variant	196	1	E → K		VAR_032651
	Natural variant	230	1	R → C		VAR_032652
	Natural variant	233	1	G → R		VAR_032653
	Natural variant	237	1	F → V		VAR_032654
	Natural variant	251	1	P → T		VAR_032655
	Natural variant	266	1	T → M: dbSNP rs1044250.		VAR_020428
	Natural variant	278	1	R → Q: dbSNP rs35061979.		VAR_032656
	Natural variant	291	1	V → M		VAR_032657
	Natural variant	293	1	L → M		VAR_032658
	Natural variant	296	1	E → V		VAR_032659
	Natural variant	307	1	P → S		VAR_032660
	Natural variant	308	1	V → M		VAR_032661
	Natural variant	336	1	R → C		VAR_032662
	Natural variant	338	1	D → E		VAR_032663
	Natural variant	349	1	W → C		VAR_032664
	Natural variant	361	1	G → R		VAR_032665
	Natural variant	361	1	G → S		VAR_032666
	Natural variant	371	1	R → Q		VAR_032667
	Natural variant	384	1	R → W		VAR_032668
Experimental info
	Sequence conflict	55 – 71	17	LREHA…SALER → CANTGAHPQSAERAGA in AAD41088. Ref.5
	Sequence conflict	60	1	E → G in BAB40692. Ref.4
	Sequence conflict	175	1	A → P in AAF62868. Ref.1
	Sequence conflict	251	1	P → S in BAD96209. Ref.7
	Sequence conflict	270	1	N → D in BAD96209. Ref.7
	Sequence conflict	277	1	L → R in BAD96244. Ref.7
	Sequence conflict	304	1	L → F in AAF62868. Ref.1
	Sequence conflict	363	1	Y → H in BAD96209. Ref.7
	Sequence conflict	389	1	P → S in AAF62868. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q9BY76-1 [UniParc]. Last modified November 8, 2002. Version 2. Checksum: 219E56FEB3F602AF	FASTA	406	45,214
	10 20 30 40 50 60 MSGAPTAGAA LMLCAATAVL LSAQGGPVQS KSPRFASWDE MNVLAHGLLQ LGQGLREHAE 70 80 90 100 110 120 RTRSQLSALE RRLSACGSAC QGTEGSTDLP LAPESRVDPE VLHSLQTQLK AQNSRIQQLF 130 140 150 160 170 180 HKVAQQQRHL EKQHLRIQHL QSQFGLLDHK HLDHEVAKPA RRKRLPEMAQ PVDPAHNVSR 190 200 210 220 230 240 LHRLPRDCQE LFQVGERQSG LFEIQPQGSP PFLVNCKMTS DGGWTVIQRR HDGSVDFNRP 250 260 270 280 290 300 WEAYKAGFGD PHGEFWLGLE KVHSITGDRN SRLAVQLRDW DGNAELLQFS VHLGGEDTAY 310 320 330 340 350 360 SLQLTAPVAG QLGATTVPPS GLSVPFSTWD QDHDLRRDKN CAKSLSGGWW FGTCSHSNLN 370 380 390 400 GQYFRSIPQQ RQKLKKGIFW KTWRGRYYPL QATTMLIQPM AAEAAS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis." Kim I., Kim H.-G., Kim H., Kim H.-H., Park S.K., Uhm C.-S., Lee Z.H., Koh G.Y. Biochem. J. 346:603-610(2000) [PubMed: 10698685] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, SUBCELLULAR LOCATION, GLYCOSYLATION, VARIANT MET-266.
[2]	"Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation." Yoon J.C., Chickering T.W., Rosen E.D., Dussault B., Qin Y., Soukas A., Friedman J.M., Holmes W.E., Spiegelman B.M. Mol. Cell. Biol. 20:5343-5349(2000) [PubMed: 10866690] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], POSSIBLE FUNCTION. Tissue: Aortic endothelium.
[3]	"Cloning of a novel gene, ANGPTL4 and the functional study in angiogenesis." Zhu H., Li J., Qin W., Yang Y., He X., Wan D., Gu J. Zhonghua Yi Xue Za Zhi 82:94-99(2002) [PubMed: 11953136] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[4]	"Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4." Ito Y., Oike Y., Yasunaga K., Hamada K., Miyata K., Matsumoto S., Sugano S., Tanihara H., Masuho Y., Suda T. Cancer Res. 63:6651-6657(2003) [PubMed: 14583458] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION. Tissue: Placenta.
[5]	"A catalogue of genes in the human dermal papilla cells as identified by expressed sequence tags." Kim M.K., Kim Y.H., Seo J.M., Lee H.M., Chung H.J., Sohn M.Y., Hwang S.Y., Im S.U., Jung E.J., Lee J.H., Kim J.C. Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Hair follicle dermal papilla.
[6]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT MET-266. Tissue: Adipose tissue.
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[9]	"Expression and function of hepatocellular carcinoma-related gene pp1158." Zhu H., Li J., Wan D., Yang Y., Qin W., Ge C., Yao M., Gu J. Zhonghua Zhong Liu Za Zhi 24:123-125(2002) [PubMed: 12015030] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[10]	"Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma." Le Jan S., Amy C., Cazes A., Monnot C., Lamande N., Favier J., Philippe J., Sibony M., Gasc J.-M., Corvol P., Germain S. Am. J. Pathol. 162:1521-1528(2003) [PubMed: 12707035] [Abstract] Cited for: DISEASE.
[11]	"Angiopoietin-like-4 is a potential angiogenic mediator in arthritis." Hermann L.M., Pinkerton M., Jennings K., Yang L., Grom A., Sowders D., Kersten S., Witte D.P., Hirsch R., Thornton S. Clin. Immunol. 115:93-101(2005) [PubMed: 15870027] [Abstract] Cited for: DISEASE.
[12]	"Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice." Xu A., Lam M.C., Chan K.W., Wang Y., Zhang J., Hoo R.L., Xu J.Y., Chen B., Chow W.S., Tso A.W., Lam K.S. Proc. Natl. Acad. Sci. U.S.A. 102:6086-6091(2005) [PubMed: 15837923] [Abstract] Cited for: POSSIBLE INVOLVEMENT IN DIABETES TYPE 2.
[13]	"Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL." Romeo S., Pennacchio L.A., Fu Y., Boerwinkle E., Tybjaerg-Hansen A., Hobbs H.H., Cohen J.C. Nat. Genet. 39:513-516(2007) [PubMed: 17322881] [Abstract] Cited for: VARIANTS LEU-5; LYS-40; ILE-41; ARG-67; LEU-72; ARG-77; LYS-167; SER-174; GLN-190; LYS-196; CYS-230; ARG-233; VAL-237; THR-251; MET-266; GLN-278; MET-291; MET-293; VAL-296; SER-307; MET-308; CYS-336; GLU-338; CYS-349; SER-361; ARG-361; GLN-371 AND TRP-384.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF169312 mRNA. Translation: AAF62868.1. AF202636 mRNA. Translation: AAG22490.1. AB056477 mRNA. Translation: BAB40692.1. AF153606 mRNA. Translation: AAD41088.1. AY358275 mRNA. Translation: AAQ88642.1. Different initiation. AK222489 mRNA. Translation: BAD96209.1. AK222524 mRNA. Translation: BAD96244.1. BC023647 mRNA. Translation: AAH23647.1.
RefSeq	NP_001034756.1. NP_647475.1.
UniGene	Hs.9613
3D structure databases
HSSP	HSSP built from PDB template 3FIB based on UniProtKB P02679.
ModBase	Search...
Genome annotation databases
Ensembl	ENSG00000167772. Homo sapiens. [Contig view]
GeneID	51129.
KEGG	hsa:51129.
Organism-specific databases
H-InvDB	HIX0027444.
HGNC	HGNC:16039. ANGPTL4.
HPA	HPA007879.
MIM	605910. gene.
PharmGKB	PA24797.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOVERGEN	Q9BY76.
Gene expression databases
ArrayExpress	Q9BY76.
CleanEx	HS_ANGPTL4.
GermOnline	ENSG00000167772. Homo sapiens.
Family and domain databases
InterPro	IPR002181. Fibrinogen_a/b/g_C. IPR014716. Fibrinogen_a/b/g_C_1. IPR014715. Fibrinogen_a/b/g_C_2. [Graphical view]
Gene3D	G3DSA:3.90.215.10. Fibrinogen_a/b/g_C_1. 1 hit. G3DSA:4.10.530.10. Fibrinogen_a/b/g_C_2. 1 hit.
Pfam	PF00147. Fibrinogen_C. 1 hit. [Graphical view]
SMART	SM00186. FBG. 1 hit. [Graphical view]
PROSITE	PS00514. FIBRINOGEN_C_1. 1 hit. PS51406. FIBRINOGEN_C_2. 1 hit. [Graphical view]
BLOCKS	Search...
ProtoNet	Search...
Other Resources
NextBio	53949.
SOURCE	Search...

Entry information

Entry name

ANGL4_HUMAN

Accession

Primary (citable) accession number: Q9BY76
Secondary accession number(s): Q53HQ6 , Q53HU1, Q6UXN0, Q9HBV4, Q9NZU4, Q9Y5B3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 8, 2002
Last sequence update:	November 8, 2002
Last modified:	November 4, 2008
This is version 67 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)