A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO

  • J Cell Biol. 2016 Dec 5;215(5):705-718. doi: 10.1083/jcb.201605121.
Gun-Hee Lee  1  2 ,  Morihisa Fujita  3 ,  Katsuyoshi Takaoka  4 ,  Yoshiko Murakami  1  2 ,  Yoshitaka Fujihara  1  2 ,  Noriyuki Kanzawa  1  2 ,  Kei-Ichi Murakami  1  2 ,  Eriko Kajikawa  5 ,  Yoko Takada  1  2 ,  Kazunobu Saito  1  2 ,  Masahito Ikawa  1  2 ,  Hiroshi Hamada  4  5 ,  Yusuke Maeda  1  2 ,  Taroh Kinoshita  6  2
Affiliations
  • 1. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 2. World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
  • 3. The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, China.
  • 4. Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
  • 5. Center for Developmental Biology, Institute of Physical and Chemical Research, Kobe, Hyogo 650-0047, Japan.
  • 6. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan [email protected].
PMID: 27881714 DOI: 10.1083/jcb.201605121
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.