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J Cell Biol. 2016 Dec 5;215(5):705-718. Epub 2016 Nov 23.

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

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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.
The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, Jiangsu 214122, China.
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.
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan


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.

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