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Protein

Angiopoietin-related protein 3

Gene

Angptl3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12671033). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (PubMed:26305978). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity; the function seems to be specific for the feeding conditions. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12909640, PubMed:16081640, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids; the cleaved N-terminal domain is more efficient than the uncleaved proprotein (PubMed:17681148). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (By similarity). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (PubMed:26305978). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR (PubMed:25954050). May stimulate hypothalamic LPL activity (PubMed:25338813).By similarity8 Publications
Involved in angiogenesis (PubMed:11877390). Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (By similarity). May increase the motility of podocytes. Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (By similarity). May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation (PubMed:20633534, PubMed:24294595, PubMed:25710887). Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (PubMed:20959605).By similarity5 Publications

GO - Molecular functioni

GO - Biological processi

  • acylglycerol homeostasis Source: BHF-UCL
  • angiogenesis Source: UniProtKB-KW
  • artery morphogenesis Source: BHF-UCL
  • cell-matrix adhesion Source: UniProtKB
  • cholesterol homeostasis Source: BHF-UCL
  • cholesterol metabolic process Source: MGI
  • fatty acid metabolic process Source: MGI
  • glycerol metabolic process Source: MGI
  • lipid homeostasis Source: MGI
  • lipid storage Source: MGI
  • negative regulation of lipoprotein lipase activity Source: MGI
  • negative regulation of phospholipase activity Source: BHF-UCL
  • phospholipid catabolic process Source: MGI
  • phospholipid homeostasis Source: BHF-UCL
  • phospholipid metabolic process Source: MGI
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of cell migration Source: UniProtKB
  • positive regulation of lipid catabolic process Source: MGI
  • positive regulation of lipid metabolic process Source: UniProtKB
  • response to hormone Source: Ensembl
  • signal transduction Source: MGI
  • triglyceride homeostasis Source: BHF-UCL
  • triglyceride metabolic process Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Angiogenesis, Cell adhesion, Lipid metabolism

Keywords - Ligandi

Heparin-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Angiopoietin-related protein 3
Alternative name(s):
Angiopoietin-like protein 3
Cleaved into the following chain:
Gene namesi
Name:Angptl3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1353627. Angptl3.

Subcellular locationi

GO - Cellular componenti

  • cell projection Source: UniProtKB-KW
  • cell surface Source: MGI
  • early endosome Source: MGI
  • extracellular region Source: MGI
  • extracellular space Source: MGI
  • Golgi apparatus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell projection, Secreted

Pathology & Biotechi

Disruption phenotypei

Low plasma levels of triglyceride, HDL cholesterol and HDL phospholipids, and non-esterified fatty acids (NEFA). Animals fed on high-fat, high-calorie (HFC) diet show reduced epididymal adipose tissue weight with no difference in adipocyte size. Hypotriglyceridemia with elevated postheparin plasma LPL activity is specifically observed in the fed state. Mice deficient in both Angptl3 and Angptl4 show an additive effect on plasma triglycerides and did not survive past 2 months of age.4 Publications

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi221 – 2211R → A: Abolishes proteolytical cleavage. 2 Publications
Mutagenesisi224 – 2241R → A: Abolishes proteolytical cleavage. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1616Sequence analysisAdd
BLAST
Chaini17 – 455439Angiopoietin-related protein 3PRO_0000009123Add
BLAST
Chaini17 – 224208ANGPTL3(17-224)2 PublicationsPRO_0000435905Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi115 – 1151N-linked (GlcNAc...)Sequence analysis
Glycosylationi226 – 2261O-linked (GlcNAc) ProbableBy similarity
Glycosylationi232 – 2321N-linked (GlcNAc...)Sequence analysis
Disulfide bondi246 ↔ 274PROSITE-ProRule annotation
Glycosylationi296 – 2961N-linked (GlcNAc...)Sequence analysis
Glycosylationi357 – 3571N-linked (GlcNAc...)Sequence analysis
Disulfide bondi394 ↔ 408PROSITE-ProRule annotation

Post-translational modificationi

In part proteolytically cleaved by proprotein convertases; proposed to be involved in activation. In primary hepatocytes is intracellularily predominantly processed by FURIN and extracellularily by FURIN and PCSK6/PACE4. In E18.5 embryos 75% of protein is found to be processed compared to 25 % in adults.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ9R182.
PRIDEiQ9R182.

PTM databases

PhosphoSiteiQ9R182.

Expressioni

Tissue specificityi

Predominantly expressed in liver, weakly expressed in kidney and lung. Expressed in podocytes (at protein level). Expressed in hypothalamic neurons (at protein level). Expressed in bone marrow sinusoidal endothelial cells (at protein level).4 Publications

Inductioni

Down-regulated by insulin and leptin. Not regulated by nutritional status (fed/fasting) Up-regulated in podocytes by puromycin. Up-regulated after feeding in the hypothalamus.4 Publications

Gene expression databases

BgeeiQ9R182.
CleanExiMM_ANGPTL3.
ExpressionAtlasiQ9R182. baseline and differential.
GenevisibleiQ9R182. MM.

Interactioni

Subunit structurei

Interacts with ANGPTL8 (By similarity). Interacts with ITGB3.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000030280.

Structurei

3D structure databases

ProteinModelPortaliQ9R182.
SMRiQ9R182. Positions 123-453.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini237 – 455219Fibrinogen C-terminalPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni17 – 207191Sufficient to inhibit LIPG/EL phospholipase activityBy similarityAdd
BLAST
Regioni17 – 165149Sufficient to inhibit LPL lipase activityBy similarity1 PublicationAdd
BLAST
Regioni32 – 5625Required for inhibition of LPL lipase activityBy similarityAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili85 – 206122Sequence analysisAdd
BLAST

Domaini

The fibrinogen C-terminal domain is sufficient to mediate endothelial cell adhesion.By similarity

Sequence similaritiesi

Contains 1 fibrinogen C-terminal domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil, Signal

Phylogenomic databases

eggNOGiKOG2579. Eukaryota.
ENOG410ZYS4. LUCA.
GeneTreeiENSGT00830000128240.
HOGENOMiHOG000015386.
HOVERGENiHBG001644.
InParanoidiQ9R182.
OMAiFSTWDHK.
OrthoDBiEOG7X9G60.
PhylomeDBiQ9R182.
TreeFamiTF329953.

Family and domain databases

Gene3Di3.90.215.10. 1 hit.
4.10.530.10. 1 hit.
InterProiIPR014716. Fibrinogen_a/b/g_C_1.
IPR014715. Fibrinogen_a/b/g_C_2.
IPR002181. Fibrinogen_a/b/g_C_dom.
[Graphical view]
PfamiPF00147. Fibrinogen_C. 1 hit.
[Graphical view]
SMARTiSM00186. FBG. 1 hit.
[Graphical view]
SUPFAMiSSF56496. SSF56496. 1 hit.
PROSITEiPS51406. FIBRINOGEN_C_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9R182-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MHTIKLFLFV VPLVIASRVD PDLSSFDSAP SEPKSRFAML DDVKILANGL
60 70 80 90 100
LQLGHGLKDF VHKTKGQIND IFQKLNIFDQ SFYDLSLRTN EIKEEEKELR
110 120 130 140 150
RTTSTLQVKN EEVKNMSVEL NSKLESLLEE KTALQHKVRA LEEQLTNLIL
160 170 180 190 200
SPAGAQEHPE VTSLKSFVEQ QDNSIRELLQ SVEEQYKQLS QQHMQIKEIE
210 220 230 240 250
KQLRKTGIQE PSENSLSSKS RAPRTTPPLQ LNETENTEQD DLPADCSAVY
260 270 280 290 300
NRGEHTSGVY TIKPRNSQGF NVYCDTQSGS PWTLIQHRKD GSQDFNETWE
310 320 330 340 350
NYEKGFGRLD GEFWLGLEKI YAIVQQSNYI LRLELQDWKD SKHYVEYSFH
360 370 380 390 400
LGSHETNYTL HVAEIAGNIP GALPEHTDLM FSTWNHRAKG QLYCPESYSG
410 420 430 440 450
GWWWNDICGE NNLNGKYNKP RTKSRPERRR GIYWRPQSRK LYAIKSSKMM

LQPTT
Length:455
Mass (Da):52,543
Last modified:May 1, 2000 - v1
Checksum:i31609D3700D3F33D
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF162224 mRNA. Translation: AAD45920.1.
BC019491 mRNA. Translation: AAH19491.1.
CCDSiCCDS38817.1.
RefSeqiNP_038941.1. NM_013913.4.
UniGeneiMm.28341.

Genome annotation databases

EnsembliENSMUST00000030280; ENSMUSP00000030280; ENSMUSG00000028553.
GeneIDi30924.
KEGGimmu:30924.
UCSCiuc008tur.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF162224 mRNA. Translation: AAD45920.1.
BC019491 mRNA. Translation: AAH19491.1.
CCDSiCCDS38817.1.
RefSeqiNP_038941.1. NM_013913.4.
UniGeneiMm.28341.

3D structure databases

ProteinModelPortaliQ9R182.
SMRiQ9R182. Positions 123-453.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000030280.

PTM databases

PhosphoSiteiQ9R182.

Proteomic databases

PaxDbiQ9R182.
PRIDEiQ9R182.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000030280; ENSMUSP00000030280; ENSMUSG00000028553.
GeneIDi30924.
KEGGimmu:30924.
UCSCiuc008tur.1. mouse.

Organism-specific databases

CTDi27329.
MGIiMGI:1353627. Angptl3.

Phylogenomic databases

eggNOGiKOG2579. Eukaryota.
ENOG410ZYS4. LUCA.
GeneTreeiENSGT00830000128240.
HOGENOMiHOG000015386.
HOVERGENiHBG001644.
InParanoidiQ9R182.
OMAiFSTWDHK.
OrthoDBiEOG7X9G60.
PhylomeDBiQ9R182.
TreeFamiTF329953.

Miscellaneous databases

NextBioi307316.
PROiQ9R182.
SOURCEiSearch...

Gene expression databases

BgeeiQ9R182.
CleanExiMM_ANGPTL3.
ExpressionAtlasiQ9R182. baseline and differential.
GenevisibleiQ9R182. MM.

Family and domain databases

Gene3Di3.90.215.10. 1 hit.
4.10.530.10. 1 hit.
InterProiIPR014716. Fibrinogen_a/b/g_C_1.
IPR014715. Fibrinogen_a/b/g_C_2.
IPR002181. Fibrinogen_a/b/g_C_dom.
[Graphical view]
PfamiPF00147. Fibrinogen_C. 1 hit.
[Graphical view]
SMARTiSM00186. FBG. 1 hit.
[Graphical view]
SUPFAMiSSF56496. SSF56496. 1 hit.
PROSITEiPS51406. FIBRINOGEN_C_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Identification of a mammalian angiopoietin-related protein expressed specifically in liver."
    Conklin D., Gilbertson D., Taft D.W., Maurer M.F., Whitmore T.E., Smith D.L., Walker K.M., Chen L.H., Wattler S., Nehls M., Lewis K.B.
    Genomics 62:477-482(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
  2. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Liver.
  3. "ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo."
    Camenisch G., Pisabarro M.T., Sherman D., Kowalski J., Nagel M., Hass P., Xie M.H., Gurney A., Bodary S., Liang X.H., Clark K., Beresini M., Ferrara N., Gerber H.P.
    J. Biol. Chem. 277:17281-17290(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  4. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  5. "Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo."
    Ono M., Shimizugawa T., Shimamura M., Yoshida K., Noji-Sakikawa C., Ando Y., Koishi R., Furukawa H.
    J. Biol. Chem. 278:41804-41809(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEOLYTIC CLEAVAGE.
  6. "A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice."
    Ando Y., Shimizugawa T., Takeshita S., Ono M., Shimamura M., Koishi R., Furukawa H.
    J. Lipid Res. 44:1216-1223(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  7. "Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor."
    Shimamura M., Matsuda M., Ando Y., Koishi R., Yasumo H., Furukawa H., Shimomura I.
    Biochem. Biophys. Res. Commun. 322:1080-1085(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  8. "Differential regulation and properties of angiopoietin-like proteins 3 and 4."
    Ge H., Cha J.Y., Gopal H., Harp C., Yu X., Repa J.J., Li C.
    J. Lipid Res. 46:1484-1490(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  9. "Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism."
    Koester A., Chao Y.B., Mosior M., Ford A., Gonzalez-DeWhitt P.A., Hale J.E., Li D., Qiu Y., Fraser C.C., Yang D.D., Heuer J.G., Jaskunas S.R., Eacho P.
    Endocrinology 146:4943-4950(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  10. "Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity."
    Fujimoto K., Koishi R., Shimizugawa T., Ando Y.
    Exp. Anim. 55:27-34(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.
  11. Cited for: DISRUPTION PHENOTYPE.
  12. Cited for: FUNCTION, PROTEOLYTIC CLEAVAGE.
  13. "Angiopoietin-like protein 3 regulates the motility and permeability of podocytes by altering nephrin expression in vitro."
    Gao X., Xu H., Liu H., Rao J., Li Y., Zha X.
    Biochem. Biophys. Res. Commun. 399:31-36(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  14. "Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases."
    Liu J., Afroza H., Rader D.J., Jin W.
    J. Biol. Chem. 285:27561-27570(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF ARG-221.
  15. "Expression of angiopoietin-like 3 associated with puromycin-induced podocyte damage."
    Jia R., Hong X., Li S., Haichun Y., Chuanming H.
    Nephron Exp. Nephrol. 115:E38-E45(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, INDUCTION.
  16. "Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche."
    Zheng J., Huynh H., Umikawa M., Silvany R., Zhang C.C.
    Blood 117:470-479(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY.
  17. "Angiopoietin-like 3 induces podocyte F-actin rearrangement through integrin alpha(V)beta(3)/FAK/PI3K pathway-mediated Rac1 activation."
    Lin Y., Rao J., Zha X.L., Xu H.
    Biomed. Res. Int. 2013:135608-135608(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  18. "Furin is the primary in vivo convertase of angiopoietin-like 3 and endothelial lipase in hepatocytes."
    Essalmani R., Susan-Resiga D., Chamberland A., Asselin M.C., Canuel M., Constam D., Creemers J.W., Day R., Gauthier D., Prat A., Seidah N.G.
    J. Biol. Chem. 288:26410-26418(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEOLYTIC CLEAVAGE, MUTAGENESIS OF ARG-221 AND ARG-224, SUBCELLULAR LOCATION.
  19. "Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3."
    Kim H.K., Shin M.S., Youn B.S., Kang G.M., Gil S.Y., Lee C.H., Choi J.H., Lim H.S., Yoo H.J., Kim M.S.
    Diabetes 64:1142-1153(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY, INDUCTION.
  20. "Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion."
    Wang Y., Gusarova V., Banfi S., Gromada J., Cohen J.C., Hobbs H.H.
    J. Lipid Res. 56:1296-1307(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  21. "A novel role of angiopoietin-like-3 associated with podocyte injury."
    Liu J., Gao X., Zhai Y., Shen Q., Sun L., Feng C., Rao J., Liu H., Zha X., Guo M., Ma D., Zhang Z., Li R., Xu H.
    Pediatr. Res. 77:732-739(2015) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH ITGB3, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
  22. Cited for: FUNCTION.

Entry informationi

Entry nameiANGL3_MOUSE
AccessioniPrimary (citable) accession number: Q9R182
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 8, 2002
Last sequence update: May 1, 2000
Last modified: May 11, 2016
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Was suggested to inhibit LPL through a direct mechanism; however, the necessary concentrations to achieve the in vitro inhibition are at least 30-fold higher than ANGPTL3 plasma concentrations.1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.