ID ANGL3_HUMAN Reviewed; 460 AA. AC Q9Y5C1; A0JLS0; B1ALJ0; B2RCW1; DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 27-MAR-2024, entry version 197. DE RecName: Full=Angiopoietin-related protein 3; DE AltName: Full=Angiopoietin-5; DE Short=ANG-5; DE AltName: Full=Angiopoietin-like protein 3; DE Contains: DE RecName: Full=ANGPTL3(17-221); DE Contains: DE RecName: Full=ANGPTL3(17-224); DE Flags: Precursor; GN Name=ANGPTL3; Synonyms=ANGPT5; ORFNames=UNQ153/PRO179; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND GLYCOSYLATION AT RP ASN-115. RC TISSUE=Liver; RX PubMed=10644446; DOI=10.1006/geno.1999.6041; RA Conklin D., Gilbertson D., Taft D.W., Maurer M.F., Whitmore T.E., RA Smith D.L., Walker K.M., Chen L.H., Wattler S., Nehls M., Lewis K.B.; RT "Identification of a mammalian angiopoietin-related protein expressed RT specifically in liver."; RL Genomics 62:477-482(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Liver; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Liver, and Skeletal muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 17-31. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [9] RP FUNCTION, GLYCOSYLATION, SUBCELLULAR LOCATION, AND DOMAIN. RX PubMed=11877390; DOI=10.1074/jbc.m109768200; RA Camenisch G., Pisabarro M.T., Sherman D., Kowalski J., Nagel M., Hass P., RA Xie M.H., Gurney A., Bodary S., Liang X.H., Clark K., Beresini M., RA Ferrara N., Gerber H.P.; RT "ANGPTL3 stimulates endothelial cell adhesion and migration via integrin RT alpha vbeta 3 and induces blood vessel formation in vivo."; RL J. Biol. Chem. 277:17281-17290(2002). RN [10] RP FUNCTION. RX PubMed=12097324; DOI=10.1074/jbc.m203215200; RA Shimizugawa T., Ono M., Shimamura M., Yoshida K., Ando Y., Koishi R., RA Ueda K., Inaba T., Minekura H., Kohama T., Furukawa H.; RT "ANGPTL3 decreases very low density lipoprotein triglyceride clearance by RT inhibition of lipoprotein lipase."; RL J. Biol. Chem. 277:33742-33748(2002). RN [11] RP FUNCTION. RX PubMed=11788823; DOI=10.1038/ng814; RA Koishi R., Ando Y., Ono M., Shimamura M., Yasumo H., Fujiwara T., RA Horikoshi H., Furukawa H.; RT "Angptl3 regulates lipid metabolism in mice."; RL Nat. Genet. 30:151-157(2002). RN [12] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=12565906; DOI=10.1016/s0006-291x(02)03058-9; RA Shimamura M., Matsuda M., Kobayashi S., Ando Y., Ono M., Koishi R., RA Furukawa H., Makishima M., Shimomura I.; RT "Angiopoietin-like protein 3, a hepatic secretory factor, activates RT lipolysis in adipocytes."; RL Biochem. Biophys. Res. Commun. 301:604-609(2003). RN [13] RP PROTEOLYTIC CLEAVAGE, FUNCTION, AND MUTAGENESIS OF 62-HIS-LYS-63; LYS-65; RP 204-ARG-ARG-205; ARG-221; ARG-224 AND ARG-235. RX PubMed=12909640; DOI=10.1074/jbc.m302861200; RA Ono M., Shimizugawa T., Shimamura M., Yoshida K., Noji-Sakikawa C., RA Ando Y., Koishi R., Furukawa H.; RT "Protein region important for regulation of lipid metabolism in RT angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo."; RL J. Biol. Chem. 278:41804-41809(2003). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-115; ASN-296 AND ASN-357. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [15] RP FUNCTION. RX PubMed=17110602; DOI=10.1161/01.atv.0000252827.51626.89; RA Shimamura M., Matsuda M., Yasumo H., Okazaki M., Fujimoto K., Kono K., RA Shimizugawa T., Ando Y., Koishi R., Kohama T., Sakai N., Kotani K., RA Komuro R., Ishida T., Hirata K., Yamashita S., Furukawa H., Shimomura I.; RT "Angiopoietin-like protein3 regulates plasma HDL cholesterol through RT suppression of endothelial lipase."; RL Arterioscler. Thromb. Vasc. Biol. 27:366-372(2007). RN [16] RP POSSIBLE INVOLVEMENT IN ATHEROSCLEROSIS. RX PubMed=17191020; DOI=10.1159/000098153; RA Hatsuda S., Shoji T., Shinohara K., Kimoto E., Mori K., Fukumoto S., RA Koyama H., Emoto M., Nishizawa Y.; RT "Association between plasma angiopoietin-like protein 3 and arterial wall RT thickness in healthy subjects."; RL J. Vasc. Res. 44:61-66(2007). RN [17] RP FUNCTION. RX PubMed=18535744; DOI=10.1111/j.1745-7270.2008.00421.x; RA Li Y., Sun L., Xu H., Fang Z., Yao W., Guo W., Rao J., Zha X.; RT "Angiopoietin-like protein 3 modulates barrier properties of human RT glomerular endothelial cells through a possible signaling pathway involving RT phosphatidylinositol-3 kinase/protein kinase B and integrin alphaVbeta3."; RL Acta Biochim. Biophys. Sin. 40:459-465(2008). RN [18] RP FUNCTION. RX PubMed=19028676; DOI=10.1074/jbc.m808477200; RA Shan L., Yu X.C., Liu Z., Hu Y., Sturgis L.T., Miranda M.L., Liu Q.; RT "The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein RT lipase activity through distinct mechanisms."; RL J. Biol. Chem. 284:1419-1424(2009). RN [19] RP FUNCTION. RX PubMed=19318355; DOI=10.1074/jbc.m807899200; RA Lee E.C., Desai U., Gololobov G., Hong S., Feng X., Yu X.C., Gay J., RA Wilganowski N., Gao C., Du L.L., Chen J., Hu Y., Zhao S., Kirkpatrick L., RA Schneider M., Zambrowicz B.P., Landes G., Powell D.R., Sonnenburg W.K.; RT "Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3) RT and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of RT lipoprotein lipase (LPL)."; RL J. Biol. Chem. 284:13735-13745(2009). RN [20] RP FUNCTION (ANGPTL3(17-221)). RX PubMed=19542565; DOI=10.1194/jlr.m900145-jlr200; RA Sonnenburg W.K., Yu D., Lee E.C., Xiong W., Gololobov G., Key B., Gay J., RA Wilganowski N., Hu Y., Zhao S., Schneider M., Ding Z.M., Zambrowicz B.P., RA Landes G., Powell D.R., Desai U.; RT "GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by RT angiopoietin-like 3 and angiopoietin-like 4."; RL J. Lipid Res. 50:2421-2429(2009). RN [21] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-296. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [22] RP FUNCTION. RX PubMed=20581395; DOI=10.1074/jbc.m110.144279; RA Liu J., Afroza H., Rader D.J., Jin W.; RT "Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through RT enhancing its cleavage by proprotein convertases."; RL J. Biol. Chem. 285:27561-27570(2010). RN [23] RP GLYCOSYLATION AT THR-226. RX PubMed=20837471; DOI=10.1074/jbc.m110.156950; RA Schjoldager K.T., Vester-Christensen M.B., Bennett E.P., Levery S.B., RA Schwientek T., Yin W., Blixt O., Clausen H.; RT "O-glycosylation modulates proprotein convertase activation of RT angiopoietin-like protein 3: possible role of polypeptide GalNAc- RT transferase-2 in regulation of concentrations of plasma lipids."; RL J. Biol. Chem. 285:36293-36303(2010). RN [24] RP INVOLVEMENT IN FHBL2. RX PubMed=20942659; DOI=10.1056/nejmoa1002926; RA Musunuru K., Pirruccello J.P., Do R., Peloso G.M., Guiducci C., Sougnez C., RA Garimella K.V., Fisher S., Abreu J., Barry A.J., Fennell T., Banks E., RA Ambrogio L., Cibulskis K., Kernytsky A., Gonzalez E., Rudzicz N., RA Engert J.C., DePristo M.A., Daly M.J., Cohen J.C., Hobbs H.H., RA Altshuler D., Schonfeld G., Gabriel S.B., Yue P., Kathiresan S.; RT "Exome sequencing, ANGPTL3 mutations, and familial combined RT hypolipidemia."; RL N. Engl. J. Med. 363:2220-2227(2010). RN [25] RP GLYCOSYLATION. RX PubMed=22566642; DOI=10.1073/pnas.1203563109; RA Schjoldager K.T., Vakhrushev S.Y., Kong Y., Steentoft C., Nudelman A.S., RA Pedersen N.B., Wandall H.H., Mandel U., Bennett E.P., Levery S.B., RA Clausen H.; RT "Probing isoform-specific functions of polypeptide GalNAc-transferases RT using zinc finger nuclease glycoengineered SimpleCells."; RL Proc. Natl. Acad. Sci. U.S.A. 109:9893-9898(2012). RN [26] RP INTERACTION WITH ANGPTL8. RX PubMed=23150577; DOI=10.1073/pnas.1217552109; RA Quagliarini F., Wang Y., Kozlitina J., Grishin N.V., Hyde R., RA Boerwinkle E., Valenzuela D.M., Murphy A.J., Cohen J.C., Hobbs H.H.; RT "Atypical angiopoietin-like protein that regulates ANGPTL3."; RL Proc. Natl. Acad. Sci. U.S.A. 109:19751-19756(2012). RN [27] RP FUNCTION. RX PubMed=23661675; DOI=10.1161/atvbaha.113.301397; RA Robciuc M.R., Maranghi M., Lahikainen A., Rader D., Bensadoun A., RA Oeoerni K., Ooerni K., Metso J., Minicocci I., Ciociola E., Ceci F., RA Montali A., Arca M., Ehnholm C., Jauhiainen M.; RT "Angptl3 deficiency is associated with increased insulin sensitivity, RT lipoprotein lipase activity, and decreased serum free fatty acids."; RL Arterioscler. Thromb. Vasc. Biol. 33:1706-1713(2013). RN [28] RP FUNCTION. RX PubMed=25495645; DOI=10.1042/bsr20140115; RA Tikka A., Soronen J., Laurila P.P., Metso J., Ehnholm C., Jauhiainen M.; RT "Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes RT results in decreased expression of gluconeogenic genes and reduced RT triacylglycerol-rich VLDL secretion upon insulin stimulation."; RL Biosci. Rep. 34:E00160-E00160(2014). RN [29] RP TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=26204133; DOI=10.1210/jc.2015-1254; RA Nidhina Haridas P.A., Soronen J., Saedevirta S., Mysore R., Quagliarini F., RA Pasternack A., Metso J., Perttilae J., Leivonen M., Smas C.M., RA Fischer-Posovszky P., Wabitsch M., Ehnholm C., Ritvos O., Jauhiainen M., RA Olkkonen V.M., Yki-Jaervinen H.; RT "Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin."; RL J. Clin. Endocrinol. Metab. 100:E1299-E1307(2015). RN [30] {ECO:0007744|PDB:6EUA} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 242-460, DISULFIDE BONDS, AND RP CHARACTERIZATION OF VARIANTS THR-259; GLN-288; PRO-292; SER-344 AND RP LYS-375. RX PubMed=29713054; DOI=10.1038/s41598-018-25237-7; RA Biterova E., Esmaeeli M., Alanen H.I., Saaranen M., Ruddock L.W.; RT "Structures of Angptl3 and Angptl4, modulators of triglyceride levels and RT coronary artery disease."; RL Sci. Rep. 8:6752-6752(2018). RN [31] RP VARIANT PHE-127. RX PubMed=22095935; DOI=10.1002/humu.21660; RA Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C., RA Kastelein J.J., Hovingh G.K., Fouchier S.W.; RT "Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic RT autosomal dominant hypercholesterolemic mutations with unexpected low LDL- RT Cl Levels."; RL Hum. Mutat. 33:448-455(2012). RN [32] RP VARIANTS THR-63; GLY-91; PHE-164; SER-173; THR-259; GLN-288; PRO-292; RP LYS-375 AND CYS-417, AND CHARACTERIZATION OF VARIANTS THR-63; GLY-91; RP PHE-164; SER-173; THR-259; ARG-GLN; PRO-292; LYS-375 AND CYS-417. RX PubMed=19075393; DOI=10.1172/jci37118; RA Romeo S., Yin W., Kozlitina J., Pennacchio L.A., Boerwinkle E., Hobbs H.H., RA Cohen J.C.; RT "Rare loss-of-function mutations in ANGPTL family members contribute to RT plasma triglyceride levels in humans."; RL J. Clin. Invest. 119:70-79(2009). RN [33] RP VARIANT SER-344, AND CHARACTERIZATION OF VARIANTS SER-173; SER-344 AND RP LYS-375. RX PubMed=25733326; DOI=10.1016/j.atherosclerosis.2015.02.031; RA Wang X., Wang D., Shan Z.; RT "Clinical and genetic analysis of a family diagnosed with familial RT hypobetalipoproteinemia in which the proband was diagnosed with diabetes RT mellitus."; RL Atherosclerosis 239:552-556(2015). RN [34] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND POSSIBLE INVOLVEMENT IN RP NEPHROTIC SYNDROME. RX PubMed=25710887; DOI=10.1038/pr.2015.38; RA Liu J., Gao X., Zhai Y., Shen Q., Sun L., Feng C., Rao J., Liu H., Zha X., RA Guo M., Ma D., Zhang Z., Li R., Xu H.; RT "A novel role of angiopoietin-like-3 associated with podocyte injury."; RL Pediatr. Res. 77:732-739(2015). CC -!- FUNCTION: Acts in part as a hepatokine that is involved in regulation CC of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, CC PubMed:23661675, PubMed:25495645). Proposed to play a role in the CC trafficking of energy substrates to either storage or oxidative tissues CC in response to food intake (By similarity). Has a stimulatory effect on CC plasma triglycerides (TG), which is achieved by suppressing plasma TG CC clearance via inhibition of LPL activity. The inhibition of LPL CC activity appears to be an indirect mechanism involving recruitment of CC proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and CC dissociation of LPL from the cell surface; the function does not CC require ANGPTL3 proteolytic cleavage but seems to be mediated by the N- CC terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, CC PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, CC causing increased plasma levels of high density lipoprotein (HDL) CC cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can CC bind to adipocytes to activate lipolysis, releasing free fatty acids CC and glycerol (PubMed:12565906). Suppresses LPL specifically in CC oxidative tissues which is required to route very low density CC lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in CC response to food; the function may involve cooperation with CC circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By CC similarity). Contributes to lower plasma levels of low density CC lipoprotein (LDL)-cholesterol by a mechanism that is independent of the CC canonical pathway implicating APOE and LDLR. May stimulate hypothalamic CC LPL activity (By similarity). {ECO:0000250|UniProtKB:Q9R182, CC ECO:0000269|PubMed:11788823, ECO:0000269|PubMed:12097324, CC ECO:0000269|PubMed:12565906, ECO:0000269|PubMed:12909640, CC ECO:0000269|PubMed:17110602, ECO:0000269|PubMed:19028676, CC ECO:0000269|PubMed:19318355, ECO:0000269|PubMed:20581395, CC ECO:0000269|PubMed:23661675, ECO:0000269|PubMed:25495645, CC ECO:0000305|PubMed:20581395}. CC -!- FUNCTION: [ANGPTL3(17-221)]: In vitro inhibits LPL activity; not CC effective on GPIHBP1-stabilized LPL. {ECO:0000269|PubMed:19542565}. CC -!- FUNCTION: Involved in angiogenesis. Binds to endothelial cells via CC integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt CC signaling pathways and induces cell adhesion and cell migration CC (PubMed:11877390). Secreted from podocytes, may modulate properties of CC glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt CC signaling (PubMed:18535744). May increase the motility of podocytes. CC May induce actin filament rearrangements in podocytes implicating CC integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic CC stem cells (HSC) and is involved in the regulation of HSC activity CC probably implicating down-regulation of IKZF1/IKAROS (By similarity). CC {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11877390, CC ECO:0000269|PubMed:18535744}. CC -!- SUBUNIT: Interacts with ANGPTL8. Interacts with ITGB3 (By similarity). CC {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:23150577}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250, CC ECO:0000305|PubMed:11877390}. Cell projection, lamellipodium CC {ECO:0000250|UniProtKB:Q9R182}. Note=Colocalized with HSPG2 and CC activated ITGB3 on podocytes. {ECO:0000250|UniProtKB:Q9R182}. CC -!- TISSUE SPECIFICITY: Expressed principally in liver. Weakly expressed in CC kidney. Binds to adipocytes. Increased expression and colocalization CC with activated ITGB3 in glomeruli of patients with nephrotic syndrome CC showing effaced podocyte foot processes (at protein level). CC {ECO:0000269|PubMed:10644446, ECO:0000269|PubMed:25710887, CC ECO:0000269|PubMed:26204133}. CC -!- INDUCTION: Down-regulated by insulin. {ECO:0000269|PubMed:26204133}. CC -!- DOMAIN: The fibrinogen C-terminal domain is sufficient to mediate CC endothelial cell adhesion. {ECO:0000269|PubMed:11877390}. CC -!- PTM: O-glycosylated at Thr-226 by GALNT2; blocks processing and CC activation by proprotein convertases. {ECO:0000269|PubMed:20837471, CC ECO:0000269|PubMed:22566642}. CC -!- PTM: In part proteolytically cleaved by proprotein convertases; CC proposed to be involved in activation. {ECO:0000269|PubMed:12909640, CC ECO:0000269|PubMed:20837471}. CC -!- DISEASE: Hypobetalipoproteinemia, familial, 2 (FHBL2) [MIM:605019]: A CC disorder of lipid metabolism characterized by less than 5th percentile CC age- and sex-specific levels of low density lipoproteins, and dietary CC fat malabsorption. Affected individuals present with combined CC hypolipidemia, consisting of extremely low plasma levels of LDL CC cholesterol, HDL cholesterol, and triglycerides. CC {ECO:0000269|PubMed:20942659}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Note=May be involved in atherosclerosis. Plasma levels are CC closely associated with arterial wall thickness. CC {ECO:0000305|PubMed:17191020}. CC -!- DISEASE: Note=May be involved in nephrotic syndrome. CC {ECO:0000305|PubMed:25710887}. CC -!- MISCELLANEOUS: Was suggested to inhibit LPL through a direct mechanism; CC however, the necessary concentration to achieve in vitro inhibition is CC at least 30-fold higher than ANGPTL3 plasma concentration. CC {ECO:0000305|PubMed:19028676, ECO:0000305|PubMed:20581395}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH07059.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF152562; AAD34156.1; -; mRNA. DR EMBL; AY358273; AAQ88640.1; -; mRNA. DR EMBL; AK315304; BAG37708.1; -; mRNA. DR EMBL; AY569015; AAS66984.1; -; Genomic_DNA. DR EMBL; FJ515851; ACS13743.1; -; Genomic_DNA. DR EMBL; CH471059; EAX06583.1; -; Genomic_DNA. DR EMBL; BC007059; AAH07059.1; ALT_SEQ; mRNA. DR EMBL; BC058287; AAH58287.1; -; mRNA. DR CCDS; CCDS622.1; -. DR RefSeq; NP_055310.1; NM_014495.3. DR PDB; 6EUA; X-ray; 2.10 A; A/B/C=242-460. DR PDBsum; 6EUA; -. DR AlphaFoldDB; Q9Y5C1; -. DR SASBDB; Q9Y5C1; -. DR SMR; Q9Y5C1; -. DR BioGRID; 118143; 9. DR IntAct; Q9Y5C1; 7. DR STRING; 9606.ENSP00000360170; -. DR ChEMBL; CHEMBL3710485; -. DR DrugBank; DB15354; Evinacumab. DR UniLectin; Q9Y5C1; -. DR GlyConnect; 1010; 2 N-Linked glycans (3 sites). DR GlyCosmos; Q9Y5C1; 8 sites, 5 glycans. DR GlyGen; Q9Y5C1; 8 sites, 2 N-linked glycans (3 sites), 3 O-linked glycans (3 sites). DR iPTMnet; Q9Y5C1; -. DR PhosphoSitePlus; Q9Y5C1; -. DR BioMuta; ANGPTL3; -. DR DMDM; 25008126; -. DR MassIVE; Q9Y5C1; -. DR PaxDb; 9606-ENSP00000360170; -. DR PeptideAtlas; Q9Y5C1; -. DR ProteomicsDB; 86339; -. DR ABCD; Q9Y5C1; 1 sequenced antibody. DR Antibodypedia; 19489; 550 antibodies from 40 providers. DR DNASU; 27329; -. DR Ensembl; ENST00000371129.4; ENSP00000360170.3; ENSG00000132855.5. DR GeneID; 27329; -. DR KEGG; hsa:27329; -. DR MANE-Select; ENST00000371129.4; ENSP00000360170.3; NM_014495.4; NP_055310.1. DR UCSC; uc001das.3; human. DR AGR; HGNC:491; -. DR CTD; 27329; -. DR DisGeNET; 27329; -. DR GeneCards; ANGPTL3; -. DR GeneReviews; ANGPTL3; -. DR HGNC; HGNC:491; ANGPTL3. DR HPA; ENSG00000132855; Tissue enriched (liver). DR MalaCards; ANGPTL3; -. DR MIM; 604774; gene. DR MIM; 605019; phenotype. DR neXtProt; NX_Q9Y5C1; -. DR OpenTargets; ENSG00000132855; -. DR Orphanet; 426; NON RARE IN EUROPE: Familial hypobetalipoproteinemia. DR PharmGKB; PA24796; -. DR VEuPathDB; HostDB:ENSG00000132855; -. DR eggNOG; KOG2579; Eukaryota. DR GeneTree; ENSGT00940000156746; -. DR HOGENOM; CLU_038628_2_0_1; -. DR InParanoid; Q9Y5C1; -. DR OMA; WKEEKHW; -. DR OrthoDB; 3134470at2759; -. DR PhylomeDB; Q9Y5C1; -. DR TreeFam; TF336658; -. DR PathwayCommons; Q9Y5C1; -. DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes. DR Reactome; R-HSA-9029558; NR1H2 & NR1H3 regulate gene expression linked to lipogenesis. DR SignaLink; Q9Y5C1; -. DR BioGRID-ORCS; 27329; 33 hits in 1144 CRISPR screens. DR ChiTaRS; ANGPTL3; human. DR GeneWiki; ANGPTL3; -. DR GenomeRNAi; 27329; -. DR Pharos; Q9Y5C1; Tclin. DR PRO; PR:Q9Y5C1; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9Y5C1; Protein. DR Bgee; ENSG00000132855; Expressed in right lobe of liver and 109 other cell types or tissues. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0062023; C:collagen-containing extracellular matrix; IBA:GO_Central. DR GO; GO:0005769; C:early endosome; IEA:Ensembl. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL. DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl. DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell. DR GO; GO:0004857; F:enzyme inhibitor activity; ISS:UniProtKB. DR GO; GO:0008083; F:growth factor activity; IDA:BHF-UCL. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0005178; F:integrin binding; IPI:UniProtKB. DR GO; GO:0004859; F:phospholipase inhibitor activity; IDA:BHF-UCL. DR GO; GO:0055090; P:acylglycerol homeostasis; IDA:BHF-UCL. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0048844; P:artery morphogenesis; ISS:BHF-UCL. DR GO; GO:0007160; P:cell-matrix adhesion; IPI:UniProtKB. DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL. DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL. DR GO; GO:0006631; P:fatty acid metabolic process; IDA:BHF-UCL. DR GO; GO:0006071; P:glycerol metabolic process; IDA:BHF-UCL. DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB. DR GO; GO:0055088; P:lipid homeostasis; IDA:BHF-UCL. DR GO; GO:0019915; P:lipid storage; IDA:BHF-UCL. DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL. DR GO; GO:0010519; P:negative regulation of phospholipase activity; IDA:BHF-UCL. DR GO; GO:0009395; P:phospholipid catabolic process; IDA:BHF-UCL. DR GO; GO:0055091; P:phospholipid homeostasis; IDA:BHF-UCL. DR GO; GO:0006644; P:phospholipid metabolic process; IDA:BHF-UCL. DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB. DR GO; GO:0050996; P:positive regulation of lipid catabolic process; IDA:BHF-UCL. DR GO; GO:0009725; P:response to hormone; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IDA:BHF-UCL. DR GO; GO:0070328; P:triglyceride homeostasis; IGI:MGI. DR CDD; cd00087; FReD; 1. DR DisProt; DP02665; -. DR Gene3D; 3.90.215.10; Gamma Fibrinogen, chain A, domain 1; 1. DR InterPro; IPR036056; Fibrinogen-like_C. DR InterPro; IPR014716; Fibrinogen_a/b/g_C_1. DR InterPro; IPR002181; Fibrinogen_a/b/g_C_dom. DR PANTHER; PTHR19143:SF222; ANGIOPOIETIN-RELATED PROTEIN 3; 1. DR PANTHER; PTHR19143; FIBRINOGEN/TENASCIN/ANGIOPOEITIN; 1. DR Pfam; PF00147; Fibrinogen_C; 1. DR SMART; SM00186; FBG; 1. DR SUPFAM; SSF56496; Fibrinogen C-terminal domain-like; 1. DR PROSITE; PS51406; FIBRINOGEN_C_2; 1. DR Genevisible; Q9Y5C1; HS. PE 1: Evidence at protein level; KW 3D-structure; Angiogenesis; Cell adhesion; Cell projection; Coiled coil; KW Direct protein sequencing; Disulfide bond; Glycoprotein; Heparin-binding; KW Lipid metabolism; Reference proteome; Secreted; Signal. FT SIGNAL 1..16 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 17..460 FT /note="Angiopoietin-related protein 3" FT /id="PRO_0000009122" FT CHAIN 17..224 FT /note="ANGPTL3(17-224)" FT /evidence="ECO:0000305|PubMed:12909640" FT /id="PRO_0000435903" FT CHAIN 17..221 FT /note="ANGPTL3(17-221)" FT /evidence="ECO:0000305|PubMed:12909640" FT /id="PRO_0000435904" FT DOMAIN 237..455 FT /note="Fibrinogen C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739" FT REGION 17..207 FT /note="Sufficient to inhibit LIPG/EL phospholipase FT activity" FT /evidence="ECO:0000269|PubMed:17110602" FT REGION 17..165 FT /note="Sufficient to inhibit LPL lipase activity" FT /evidence="ECO:0000269|PubMed:12909640" FT REGION 32..56 FT /note="Required for inhibition of LPL lipase activity" FT /evidence="ECO:0000269|PubMed:19318355" FT COILED 85..210 FT /evidence="ECO:0000255" FT CARBOHYD 115 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:10644446, FT ECO:0000269|PubMed:16335952" FT CARBOHYD 226 FT /note="O-linked (GalNAc) threonine" FT /evidence="ECO:0000269|PubMed:20837471" FT CARBOHYD 296 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:19159218" FT CARBOHYD 357 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952" FT DISULFID 246..274 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739" FT DISULFID 394..408 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739" FT VARIANT 63 FT /note="K -> T (associated with low plasma triglyceride FT level; fails to suppress LPL activity in vitro; FT dbSNP:rs146749211)" FT /evidence="ECO:0000269|PubMed:19075393" FT /id="VAR_075670" FT VARIANT 91 FT /note="E -> G (associated with low plasma triglyceride FT level; fails to suppress LPL activity in vitro; FT dbSNP:rs139334976)" FT /evidence="ECO:0000269|PubMed:19075393" FT /id="VAR_075671" FT VARIANT 127 FT /note="L -> F (in dbSNP:rs72649573)" FT /evidence="ECO:0000269|PubMed:22095935" FT /id="VAR_067283" FT VARIANT 164 FT /note="L -> F (associated with low plasma triglyceride FT level; fails to suppress LPL activity in vitro; FT dbSNP:rs775976787)" FT /evidence="ECO:0000269|PubMed:19075393" FT /id="VAR_075672" FT VARIANT 173 FT /note="N -> S (associated with low plasma triglyceride FT level; fails to suppress LPL activity in vitro; no effect FT on protein secretion; dbSNP:rs149624466)" FT /evidence="ECO:0000269|PubMed:19075393, FT ECO:0000269|PubMed:25733326" FT /id="VAR_075673" FT VARIANT 259 FT /note="M -> T (common allele in African americans; FT associated with low plasma triglyceride level; fails to FT suppress LPL activity in vitro; no effect on protein FT folding; dbSNP:rs77871363)" FT /evidence="ECO:0000269|PubMed:19075393, FT ECO:0000269|PubMed:29713054" FT /id="VAR_075674" FT VARIANT 288 FT /note="R -> Q (abolishes protein secretion; associated with FT low plasma triglyceride level; dbSNP:rs763904695)" FT /evidence="ECO:0000269|PubMed:19075393, FT ECO:0000269|PubMed:29713054" FT /id="VAR_075675" FT VARIANT 288 FT /note="Missing (abolishes protein secretion; associated FT with low plasma triglyceride level)" FT /evidence="ECO:0000269|PubMed:19075393" FT /id="VAR_075676" FT VARIANT 292 FT /note="S -> P (abolishes protein secretion; associated with FT low plasma triglyceride level; dbSNP:rs138899888)" FT /evidence="ECO:0000269|PubMed:19075393, FT ECO:0000269|PubMed:29713054" FT /id="VAR_075677" FT VARIANT 344 FT /note="Y -> S (abolishes protein secretion; associated with FT low plasma triglyceride level; dbSNP:rs1334979946)" FT /evidence="ECO:0000269|PubMed:25733326, FT ECO:0000269|PubMed:29713054" FT /id="VAR_075678" FT VARIANT 375 FT /note="E -> K (abolishes protein secretion; associated with FT low plasma triglyceride level; dbSNP:rs768802285)" FT /evidence="ECO:0000269|PubMed:19075393, FT ECO:0000269|PubMed:25733326, ECO:0000269|PubMed:29713054" FT /id="VAR_075679" FT VARIANT 417 FT /note="Y -> C (abolishes protein secretion; associated with FT low plasma triglyceride level; dbSNP:rs376210525)" FT /evidence="ECO:0000269|PubMed:19075393" FT /id="VAR_075680" FT VARIANT 418 FT /note="N -> Y (in dbSNP:rs4145257)" FT /id="VAR_049071" FT MUTAGEN 62..63 FT /note="HK->IN: Abolishes effect on plasma triglyceride FT level; when associated with N-65." FT /evidence="ECO:0000269|PubMed:12909640" FT MUTAGEN 63 FT /note="K->N: Abolishes inhibitory effect on LIPG/EL FT phospholipase activity; when associated with N-65." FT /evidence="ECO:0000269|PubMed:17110602" FT MUTAGEN 65 FT /note="K->N: Abolishes effect on plasma triglyceride level; FT when associated with 62-I-N-63." FT /evidence="ECO:0000269|PubMed:12909640" FT MUTAGEN 65 FT /note="K->N: Abolishes inhibitory effect on LIPG/EL FT phospholipase activity; when associated with N-63." FT /evidence="ECO:0000269|PubMed:17110602" FT MUTAGEN 204..205 FT /note="RR->TT: Abolishes proteolytical cleavage and effect FT on plasma triglyceride levels, keeps in vitro inactivation FT of LPL activity; when associated with S-221; S-224 and FT S-235." FT /evidence="ECO:0000269|PubMed:12909640" FT MUTAGEN 221 FT /note="R->ST: Abolishes proteolytical cleavage and effect FT on plasma triglyceride levels, keeps in vitro inactivation FT of LPL activity; when associated with 204-T-T-205; S-224 FT and S-235." FT /evidence="ECO:0000269|PubMed:12909640" FT MUTAGEN 224 FT /note="R->S: Abolishes proteolytical cleavage and effect on FT plasma triglyceride levels, keeps in vitro inactivation of FT LPL activity; when associated with 204-T-T-205; S-221 and FT S-235." FT /evidence="ECO:0000269|PubMed:12909640" FT MUTAGEN 235 FT /note="R->T: Abolishes proteolytical cleavage and effect on FT plasma triglyceride levels, keeps in vitro inactivation of FT LPL activity; when associated with 204-T-T-205; S-221 and FT S-224." FT /evidence="ECO:0000269|PubMed:12909640" FT CONFLICT 134 FT /note="L -> P (in Ref. 3; BAG37708)" FT /evidence="ECO:0000305" FT HELIX 246..251 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 256..262 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 270..277 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 280..291 FT /evidence="ECO:0007829|PDB:6EUA" FT HELIX 299..304 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 306..308 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 311..314 FT /evidence="ECO:0007829|PDB:6EUA" FT HELIX 317..324 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 329..337 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 342..351 FT /evidence="ECO:0007829|PDB:6EUA" FT HELIX 354..356 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 360..369 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 375..377 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 379..383 FT /evidence="ECO:0007829|PDB:6EUA" FT HELIX 395..397 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 398..400 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 402..404 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 431..435 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 437..439 FT /evidence="ECO:0007829|PDB:6EUA" FT STRAND 441..453 FT /evidence="ECO:0007829|PDB:6EUA" SQ SEQUENCE 460 AA; 53637 MW; 6279465FEEB91F56 CRC64; MFTIKLLLFI VPLVISSRID QDNSSFDSLS PEPKSRFAML DDVKILANGL LQLGHGLKDF VHKTKGQIND IFQKLNIFDQ SFYDLSLQTS EIKEEEKELR RTTYKLQVKN EEVKNMSLEL NSKLESLLEE KILLQQKVKY LEEQLTNLIQ NQPETPEHPE VTSLKTFVEK QDNSIKDLLQ TVEDQYKQLN QQHSQIKEIE NQLRRTSIQE PTEISLSSKP RAPRTTPFLQ LNEIRNVKHD GIPAECTTIY NRGEHTSGMY AIRPSNSQVF HVYCDVISGS PWTLIQHRID GSQNFNETWE NYKYGFGRLD GEFWLGLEKI YSIVKQSNYV LRIELEDWKD NKHYIEYSFY LGNHETNYTL HLVAITGNVP NAIPENKDLV FSTWDHKAKG HFNCPEGYSG GWWWHDECGE NNLNGKYNKP RAKSKPERRR GLSWKSQNGR LYSIKSTKML IHPTDSESFE //