{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:09:22Z","timestamp":1789693762347,"version":"4.0.1"},"reference-count":38,"publisher":"Rockefeller University Press","issue":"5","funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20140141"],"award-info":[{"award-number":["BK20140141"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,12,5]]},"abstract":"<jats:p>Glycosylphosphatidylinositol-anchored proteins (GPI-APs) can be shed from the cell membrane by GPI cleavage. In this study, we report a novel GPI-processing enzyme, termed post-glycosylphosphatidylinositol attachment to proteins 6 (PGAP6), which is a GPI-specific phospholipase A2 mainly localized at the cell surface. CRIPTO, a GPI-AP, which plays critical roles in early embryonic development by acting as a Nodal coreceptor, is a highly sensitive substrate of PGAP6, whereas CRYPTIC, a close homologue of CRIPTO, is not sensitive. CRIPTO processed by PGAP6 was released as a lysophosphatidylinositol-bearing form, which is further cleaved by phospholipase D. CRIPTO shed by PGAP6 was active as a coreceptor in Nodal signaling, whereas cell-associated CRIPTO activity was reduced when PGAP6 was expressed. Homozygous Pgap6 knockout mice showed defects in early embryonic development, particularly in the formation of the anterior\u2013posterior axis, which are common features with Cripto knockout embryos. These results suggest PGAP6 plays a critical role in Nodal signaling modulation through CRIPTO shedding.<\/jats:p>","DOI":"10.1083\/jcb.201605121","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T10:06:28Z","timestamp":1479895588000},"page":"705-718","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO"],"prefix":"10.1083","volume":"215","author":[{"given":"Gun-Hee","family":"Lee","sequence":"first","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morihisa","family":"Fujita","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, China 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2499-0593","authenticated-orcid":false,"given":"Katsuyoshi","family":"Takaoka","sequence":"additional","affiliation":[{"name":"Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Murakami","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Fujihara","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Kanzawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei-ichi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Kajikawa","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology, Institute of Physical and Chemical Research, Kobe, Hyogo 650-0047, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Takada","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunobu","family":"Saito","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-6217","authenticated-orcid":false,"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Hamada","sequence":"additional","affiliation":[{"name":"Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan 3"},{"name":"Center for Developmental Biology, Institute of Physical and Chemical Research, Kobe, Hyogo 650-0047, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4601-497X","authenticated-orcid":false,"given":"Yusuke","family":"Maeda","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7166-7257","authenticated-orcid":false,"given":"Taroh","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan 1"},{"name":"World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,11,23]]},"reference":[{"key":"2023072308581544700_bib1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S0925-4773(97)00125-1","article-title":"Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula","volume":"68","author":"Belo","year":"1997","journal-title":"Mech. Dev."},{"key":"2023072308581544700_bib2","doi-asserted-by":"publisher","first-page":"5539","DOI":"10.1242\/dev.02157","article-title":"Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis","volume":"132","author":"Chu","year":"2005","journal-title":"Development."},{"key":"2023072308581544700_bib3","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1126\/science.1231143","article-title":"Multiplex genome engineering using CRISPR\/Cas systems","volume":"339","author":"Cong","year":"2013","journal-title":"Science."},{"key":"2023072308581544700_bib4","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.2217\/fon.10.68","article-title":"Cripto-1: An embryonic gene that promotes tumorigenesis","volume":"6","author":"de Castro","year":"2010","journal-title":"Future Oncol."},{"key":"2023072308581544700_bib5","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/27215","article-title":"Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo","volume":"395","author":"Ding","year":"1998","journal-title":"Nature."},{"key":"2023072308581544700_bib6","first-page":"Unit 12 15","article-title":"Detection of glycophospholipid anchors on proteins","volume-title":"Curr. Protoc. Protein Sci.","author":"Doering","year":"2001"},{"key":"2023072308581544700_bib7","first-page":"143","article-title":"Glycosylphosphatidylinositol anchors","volume-title":"Essentials of Glycobiology.","author":"Ferguson","year":"2009","edition":"Second edition"},{"key":"2023072308581544700_bib8","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1194\/jlr.R063032","article-title":"GPI-AP release in cellular, developmental, and reproductive biology","volume":"57","author":"Fujihara","year":"2016","journal-title":"J. Lipid Res."},{"key":"2023072308581544700_bib9","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s11248-012-9635-x","article-title":"Production of mouse pups from germline transmission-failed knockout chimeras","volume":"22","author":"Fujihara","year":"2013","journal-title":"Transgenic Res."},{"key":"2023072308581544700_bib10","doi-asserted-by":"publisher","first-page":"8111","DOI":"10.1073\/pnas.1222166110","article-title":"Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa","volume":"110","author":"Fujihara","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072308581544700_bib11","doi-asserted-by":"publisher","first-page":"5253","DOI":"10.1091\/mbc.E06-08-0715","article-title":"PER1 is required for GPI-phospholipase A2 activity and involved in lipid remodeling of GPI-anchored proteins","volume":"17","author":"Fujita","year":"2006","journal-title":"Mol. Biol. Cell."},{"key":"2023072308581544700_bib12","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.cell.2009.08.040","article-title":"GPI glycan remodeling by PGAP5 regulates transport of GPI-anchored proteins from the ER to the Golgi","volume":"139","author":"Fujita","year":"2009","journal-title":"Cell."},{"key":"2023072308581544700_bib13","doi-asserted-by":"publisher","first-page":"35099","DOI":"10.1074\/jbc.274.49.35099","article-title":"Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol","volume":"274","author":"Hong","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2023072308581544700_bib14","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.modgep.2006.01.010","article-title":"Localization of Brachyury (T) in embryonic and extraembryonic tissues during mouse gastrulation","volume":"6","author":"Inman","year":"2006","journal-title":"Gene Expr. Patterns."},{"key":"2023072308581544700_bib15","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/nm1179","article-title":"Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization","volume":"11","author":"Kondoh","year":"2005","journal-title":"Nat. Med."},{"key":"2023072308581544700_bib16","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1042\/bj2790483","article-title":"Factors affecting the ability of glycosylphosphatidylinositol-specific phospholipase D to degrade the membrane anchors of cell surface proteins","volume":"279","author":"Low","year":"1991","journal-title":"Biochem. J."},{"key":"2023072308581544700_bib17","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1091\/mbc.E06-10-0885","article-title":"Fatty acid remodeling of GPI-anchored proteins is required for their raft association","volume":"18","author":"Maeda","year":"2007","journal-title":"Mol. Biol. Cell."},{"key":"2023072308581544700_bib18","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1242\/bio.20121982","article-title":"Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly","volume":"1","author":"McKean","year":"2012","journal-title":"Biol. Open."},{"key":"2023072308581544700_bib19","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0925-4773(99)00235-X","article-title":"Membrane-anchorage of Cripto protein by glycosylphosphatidylinositol and its distribution during early mouse development","volume":"90","author":"Minchiotti","year":"2000","journal-title":"Mech. Dev."},{"key":"2023072308581544700_bib20","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1242\/dev.128.22.4501","article-title":"Structure-function analysis of the EGF-CFC family member Cripto identifies residues essential for nodal signalling","volume":"128","author":"Minchiotti","year":"2001","journal-title":"Development."},{"key":"2023072308581544700_bib21","doi-asserted-by":"publisher","first-page":"15834","DOI":"10.1074\/jbc.272.25.15834","article-title":"Expression cloning of PIG-L, a candidate N-acetylglucosaminyl-phosphatidylinositol deacetylase","volume":"272","author":"Nakamura","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023072308581544700_bib22","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s10048-013-0384-7","article-title":"PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy","volume":"15","author":"Ohba","year":"2014","journal-title":"Neurogenetics."},{"key":"2023072308581544700_bib23","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1083\/jcb.200303010","article-title":"Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells","volume":"163","author":"Parisi","year":"2003","journal-title":"J. Cell Biol."},{"key":"2023072308581544700_bib24","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1126\/science.1231921","article-title":"GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK","volume":"339","author":"Park","year":"2013","journal-title":"Science."},{"key":"2023072308581544700_bib25","doi-asserted-by":"publisher","first-page":"6991","DOI":"10.1021\/bi8006324","article-title":"The glycosylphosphatidylinositol anchor: A complex membrane-anchoring structure for proteins","volume":"47","author":"Paulick","year":"2008","journal-title":"Biochemistry."},{"key":"2023072308581544700_bib26","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1745-6150-6-37","article-title":"CREST--a large and diverse superfamily of putative transmembrane hydrolases","volume":"6","author":"Pei","year":"2011","journal-title":"Biol. Direct."},{"key":"2023072308581544700_bib27","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S1097-2765(00)80401-3","article-title":"Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2","volume":"5","author":"Saijoh","year":"2000","journal-title":"Mol. Cell."},{"key":"2023072308581544700_bib28","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1194\/jlr.M034421","article-title":"Implications of lipid moiety in oligomerization and immunoreactivities of GPI-anchored proteins","volume":"54","author":"Seong","year":"2013","journal-title":"J. Lipid Res."},{"key":"2023072308581544700_bib29","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1242\/dev.000166","article-title":"Nodal signaling: developmental roles and regulation","volume":"134","author":"Shen","year":"2007","journal-title":"Development."},{"key":"2023072308581544700_bib30","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/S0168-9525(00)02006-0","article-title":"The EGF-CFC gene family in vertebrate development","volume":"16","author":"Shen","year":"2000","journal-title":"Trends Genet."},{"key":"2023072308581544700_bib31","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1038\/nchembio.1028","article-title":"Transient GPI-anchored protein homodimers are units for raft organization and function","volume":"8","author":"Suzuki","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"2023072308581544700_bib32","doi-asserted-by":"publisher","first-page":"14256","DOI":"10.1074\/jbc.M313755200","article-title":"Inositol deacylation of glycosylphosphatidylinositol-anchored proteins is mediated by mammalian PGAP1 and yeast Bst1p","volume":"279","author":"Tanaka","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2023072308581544700_bib33","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1091\/mbc.E05-11-1005","article-title":"PGAP2 is essential for correct processing and stable expression of GPI-anchored proteins","volume":"17","author":"Tashima","year":"2006","journal-title":"Mol. Biol. Cell."},{"key":"2023072308581544700_bib34","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1007\/s00018-005-5503-7","article-title":"Nodal signals pattern vertebrate embryos","volume":"63","author":"Tian","year":"2006","journal-title":"Cell. Mol. Life Sci."},{"key":"2023072308581544700_bib35","doi-asserted-by":"publisher","first-page":"31643","DOI":"10.1074\/jbc.M702713200","article-title":"Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration","volume":"282","author":"Watanabe","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2023072308581544700_bib36","first-page":"75","article-title":"Whole mount in situ hybridization of vertebrate embryos","volume-title":"In Situ Hybridization: A Practical Approach.","author":"Wilkinson","year":"1992","edition":"Second edition"},{"key":"2023072308581544700_bib37","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1242\/dev.126.3.483","article-title":"Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes","volume":"126","author":"Xu","year":"1999","journal-title":"Development."},{"key":"2023072308581544700_bib38","doi-asserted-by":"publisher","first-page":"4439","DOI":"10.1128\/MCB.22.13.4439-4449.2002","article-title":"Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway","volume":"22","author":"Yan","year":"2002","journal-title":"Mol. Cell. Biol."}],"container-title":["Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/215\/5\/705\/1596632\/jcb_201605121.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/215\/5\/705\/1596632\/jcb_201605121.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,23]],"date-time":"2023-07-23T05:00:39Z","timestamp":1690088439000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/215\/5\/705\/38773\/A-GPI-processing-phospholipase-A2-PGAP6-modulates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,23]]},"references-count":38,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,12,5]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.201605121","relation":{},"ISSN":["0021-9525","1540-8140"],"issn-type":[{"value":"0021-9525","type":"print"},{"value":"1540-8140","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,23]]}}}