Abstract
PGAP6, also known as TMEM8A, is a phospholipase A2 with specificity to glycosylphosphatidylinositol (GPI) and expressed on the surface of various cells. CRIPTO, a GPI-anchored co-receptor for a morphogenic factor Nodal, is a sensitive substrate of PGAP6. PGAP6-mediated shedding of CRIPTO plays a critical role in an early stage of embryogenesis. In contrast, CRYPTIC, a close family member of CRIPTO, is resistant to PGAP6. In this report, chimeras between CRIPTO and CRYPTIC and truncate mutants of PGAP6 were used to demonstrate that the Cripto-1/FRL1/Cryptic domain of CRIPTO is recognized by an N-terminal domain of PGAP6 for processing. We also report that among 56 human GPI-anchored proteins tested, only glypican 3, prostasin, SPACA4, and contactin-1, in addition to CRIPTO, are sensitive to PGAP6, indicating that PGAP6 has a narrow specificity toward various GPI-anchored proteins.
Highlights
Glycosylphosphatidylinositol (GPI)–anchored proteins (GPI-APs) are tethered to the outer leaflet of plasma membrane by a covalently linked glycolipid [1]
The chimeric cDNAs were transfected into Chinese hamster ovary (CHO) 3B2A cells with either an empty vector or PGAP6 cDNA, and the cell-surface levels of the chimeric proteins were determined by flow cytometry (Fig. 1)
If a chimera is sensitive to PGAP6, one acyl-chain will be removed from the GPI anchor, and the lipid moiety becomes lyso-PI
Summary
Glycosylphosphatidylinositol (GPI)–anchored proteins (GPI-APs) are tethered to the outer leaflet of plasma membrane by a covalently linked glycolipid [1]. There are several combinations of a select GPI-AP and a cognate GPIase with particular biological significance, such as testis-specific angiotensin-converting enzyme (tACE) cleaving the GPI anchors of TEX101 and LY6K in sperm [2, 3] by its putative endomannosidase activity [4]. Shedding of these GPI-APs from sperm is critical for sperm maturation [3]. CRYPTIC is another GPI-anchored, co-receptor for Nodal that plays a role in early embryonic development, in the generation of the left–right axis [16]. We aimed to determine whether CRIPTO is the only substrate of PGAP6 among more than 150 human GPI-APs
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