title: A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO.
abstract: 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-posterior axis, which are common features with Cripto knockout embryos. These results suggest PGAP6 plays a critical role in Nodal signaling modulation through CRIPTO shedding.
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Gun-Hee
authors.initials: GH
authors.lastname: Lee
authors.affiliation: The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, China.
authors.forename: Morihisa
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuyoshi
authors.identifier: http://orcid.org/0000-0002-2499-0593
authors.initials: K
authors.lastname: Takaoka
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujihara
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kanzawa
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kei-Ichi
authors.initials: KI
authors.lastname: Murakami
authors.affiliation: Center for Developmental Biology, Institute of Physical and Chemical Research, Kobe, Hyogo 650-0047, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Kajikawa
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Saito
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masahito
authors.identifier: http://orcid.org/0000-0001-9859-6217
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.|Center for Developmental Biology, Institute of Physical and Chemical Research, Kobe, Hyogo 650-0047, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yusuke
authors.identifier: http://orcid.org/0000-0003-4601-497X
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan tkinoshi@biken.osaka-u.ac.jp.|World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Taroh
authors.identifier: http://orcid.org/0000-0001-7166-7257
authors.initials: T
authors.lastname: Kinoshita
mesh_terms: D000818:Animals; D019521:Body Patterning; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D058851:GPI-Linked Proteins / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D055457:Nodal Protein / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D010770:Phosphotransferases / Q000235:genetics; D015398:Signal Transduction
chemical_list: D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D055457:Nodal Protein; C070636:TDGF1 protein, human; C414584:TMEM8A protein, human; C561296:PIGN protein, human; D010770:Phosphotransferases; D054467:Phospholipases A2; C484857:PGAP1 protein, human; D010744:Phosphoric Monoester Hydrolases