{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCellular homeostasis involves multiple tightly regulated processes, including the degradation of macromolecules by lysosomes as orchestrated by networks such as the CLEAR system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel to these degradation pathways, precise modulation of cell surface protein activity is essential for signaling events that govern development and tissue patterning.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have identified PGAP6 as a novel glycosylphosphatidylinositol (GPI)‐specific phospholipase A2 predominantly expressed at the cell surface."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " PGAP6 selectively processes certain GPI-anchored proteins – most notably CRIPTO, a critical co-receptor for the morphogen Nodal – by cleaving its GPI anchor to generate a lysophosphatidylinositol-bearing intermediate. This intermediate is subsequently further cleaved by phospholipase D, resulting in the shedding of soluble, yet functionally active, CRIPTO. The processing of CRIPTO by PGAP6 reduces its cell-associated activity while enhancing its ability to act in Nodal signaling; the importance of this mechanism is underscored by early embryonic defects, including improper anterior-posterior axis formation, observed in homozygous Pgap6 knockout mice.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther mechanistic insights reveal that PGAP6, also known as TMEM8A, exhibits narrow substrate specificity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Domain-mapping studies have demonstrated that the N-terminal domain of PGAP6 recognizes the Cripto-1/FRL1/Cryptic domain within CRIPTO, a feature that distinguishes it from its close homolog, CRYPTIC, which is resistant to PGAP6-mediated shedding. In addition to CRIPTO, only a limited number of other GPI-anchored proteins – including glypican 3, prostasin, SPACA4, and contactin-1 – are susceptible to processing by PGAP6. This selectivity supports the concept that PGAP6 plays a critical and specialized role in modulating cell surface protein signaling, particularly during key developmental stages.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michela Palmieri, Soren Impey, Hyojin Kang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr306"}], "href": "https://doi.org/10.1093/hmg/ddr306"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21752829"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21752829"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Gun-Hee Lee, Morihisa Fujita, Katsuyoshi Takaoka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A GPI processing phospholipase A2, PGAP6, modulates Nodal signaling in embryos by shedding CRIPTO."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201605121"}], "href": "https://doi.org/10.1083/jcb.201605121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27881714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27881714"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gun-Hee Lee, Morihisa Fujita, Hideki Nakanishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PGAP6, a GPI-specific phospholipase A2, has narrow substrate specificity against GPI-anchored proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA120.014643"}], "href": "https://doi.org/10.1074/jbc.RA120.014643"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32816994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32816994"}]}]}]}