GPI-AP release in cellular, developmental, and reproductive biology
2015; Elsevier BV; Volume: 57; Issue: 4 Linguagem: Inglês
10.1194/jlr.r063032
ISSN1539-7262
AutoresYoshitaka Fujihara, Masahito Ikawa,
Tópico(s)Signaling Pathways in Disease
ResumoGlycosylphosphatidylinositol-anchored proteins (GPI-APs) contain a covalently linked GPI anchor located on outer cell membranes. GPI-APs are ubiquitously conserved from protozoa to vertebrates and are critical for physiological events such as development, immunity, and neurogenesis in vertebrates. Both membrane-anchored and soluble GPI-APs play a role in regulating their protein conformation and functional properties. Several pathways mediate the release of GPI-APs from the plasma membrane by vesiculation or cleavage. Phospholipases and putative substrate-specific GPI-AP-releasing enzymes, such as NOTUM, glycerophosphodiesterase 2, and angiotensin-converting enzyme, have been characterized in mammals. Here, the protein modifications resulting from the cleavage of the GPI anchor are discussed in the context of its physiological functions. Glycosylphosphatidylinositol-anchored proteins (GPI-APs) contain a covalently linked GPI anchor located on outer cell membranes. GPI-APs are ubiquitously conserved from protozoa to vertebrates and are critical for physiological events such as development, immunity, and neurogenesis in vertebrates. Both membrane-anchored and soluble GPI-APs play a role in regulating their protein conformation and functional properties. Several pathways mediate the release of GPI-APs from the plasma membrane by vesiculation or cleavage. Phospholipases and putative substrate-specific GPI-AP-releasing enzymes, such as NOTUM, glycerophosphodiesterase 2, and angiotensin-converting enzyme, have been characterized in mammals. Here, the protein modifications resulting from the cleavage of the GPI anchor are discussed in the context of its physiological functions. Eukaryotic organisms produce many membrane proteins that are anchored to the outer cell membrane by glycosylphosphatidylinositol (GPI). GPI-anchored proteins (GPI-APs) have unique structures that contain mannose, glucosamine, ethanolamine, and phosphatidylinositol (1Ferguson M.A.J. Kinoshita T. Hart G.W. et al.Glycosylphosphatidylinositol anchors.in: Varki A. Cummings R.D. Esko J.D. In Essentials of Glycobiology. Cold Spring Harbor Press, Cold Spring Harbor,NY2009Google Scholar). Although they have similar core backbone structures, GPI-APs are a functionally diverse family of molecules that includes hydrolytic enzymes, adhesion molecules, receptors, protease inhibitors, and complement regulatory proteins (2Kinoshita T. Biosynthesis and deficiencies of glycosylphosphatidylinositol.Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2014; 90: 130-143Crossref PubMed Scopus (80) Google Scholar). GPI-APs are released from the cell surface by bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) (3Ikezawa H. Glycosylphosphatidylinositol (GPI)-anchored proteins.Biol. Pharm. Bull. 2002; 25: 409-417Crossref PubMed Scopus (223) Google Scholar). In mammals, GPI-APs are released and taken up by both vesiculation-mediated and non-vesiculation-mediated mechanisms (4Tsai Y.H. Liu X. Seeberger P.H. Chemical biology of glycosylphosphatidylinositol anchors.Angew. Chem. Int. Ed. Engl. 2012; 51: 11438-11456Crossref PubMed Scopus (0) Google Scholar). Several putative substrate-specific enzymes release GPI-APs from the cell surface (5Park S. Lee C. Sabharwal P. Zhang M. Meyers C.L. Sockanathan S. GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK.Science. 2013; 339: 324-328Crossref PubMed Scopus (59) Google Scholar, 6Fujihara Y. Tokuhiro K. Muro Y. Kondoh G. Araki Y. Ikawa M. Okabe M. Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa.Proc. Natl. Acad. Sci. USA. 2013; 110: 8111-8116Crossref PubMed Scopus (0) Google Scholar, 7Kondoh G. Tojo H. Nakatani Y. Komazawa N. Murata C. Yamagata K. Maeda Y. Kinoshita T. Okabe M. Taguchi R. et al.Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization.Nat. Med. 2005; 11: 160-166Crossref PubMed Scopus (179) Google Scholar, 8Kreuger J. Perez L. Giraldez A.J. Cohen S.M. Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity.Dev. Cell. 2004; 7: 503-512Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). Thus, GPI-anchor release may be required for different biological functions and regulatory mechanisms. In this review, we will focus on the significance of GPI-AP release in cellular, developmental, and reproductive biology (Table 1).TABLE 1GPI-APs and GPIase factors involved in cleavage of the GPI anchor from the cell surfaceGPI-APsGPI-AP Releasing FactorsDomain Responsible for GPIase ActivityPhenotype of GPI-AP KO MiceReferencesPLUAR/uPARGPLD1/GPI-PLDCatalytic domainMild phenotype(18Wilhelm O.G. Wilhelm S. Escott G.M. Lutz V. Magdolen V. Schmitt M. Rifkin D.B. Wilson E.L. Graeff H. Brunner G. Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression.J. Cell. Physiol. 1999; 180: 225-235Crossref PubMed Scopus (124) Google Scholar, 19Bugge T.H. Suh T.T. Flick M.J. Daugherty C.C. Romer J. Solberg H. Ellis V. Dano K. Degen J.L. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility.J. Biol. Chem. 1995; 270: 16886-16894Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar)CEACAM5/CEAGPLD1/GPI-PLDCatalytic domainNot determinedaHas not been reported.(25Yamamoto Y. Hirakawa E. Mori S. Hamada Y. Kawaguchi N. Matsuura N. Cleavage of carcinoembryonic antigen induces metastatic potential in colorectal carcinoma.Biochem. Biophys. Res. Commun. 2005; 333: 223-229Crossref PubMed Scopus (24) Google Scholar)PRSS8/prostasinGPLD1/GPI-PLDCatalytic domainEmbryonic lethality(29Verghese G.M. Gutknecht M.F. Caughey G.H. Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor.Am. J. Physiol. Cell Physiol. 2006; 291: C1258-C1270Crossref PubMed Scopus (55) Google Scholar, 31Hummler E. Dousse A. Rieder A. Stehle J.C. Rubera I. Osterheld M.C. Beermann F. Frateschi S. Charles R.P. The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation.PLoS One. 2013; 8: e55796Crossref PubMed Scopus (15) Google Scholar)TDGF1/CRIPTO-1GPLD1/GPI-PLDCatalytic domainEmbryonic lethality(37Watanabe K. Bianco C. Strizzi L. Hamada S. Mancino M. Bailly V. Mo W. Wen D. Miatkowski K. Gonzales M. et al.Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration.J. Biol. Chem. 2007; 282: 31643-31655Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 38Ding J. Yang L. Yan Y.T. Chen A. Desai N. Wynshaw-Boris A. Shen M.M. Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo.Nature. 1998; 395: 702-707Crossref PubMed Scopus (375) Google Scholar)GPC3 (glypicans)NOTUMNot determinedaHas not been reported.Postnatal lethality(44Cano-Gauci D.F. Song H.H. Yang H. McKerlie C. Choo B. Shi W. Pullano R. Piscione T.D. Grisaru S. Soon S. et al.Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.J. Cell Biol. 1999; 146: 255-264Crossref PubMed Scopus (271) Google Scholar, 58Traister A. Shi W. Filmus J. Mammalian Notum induces the release of glypicans and other GPI-anchored proteins from the cell surface.Biochem. J. 2008; 410: 503-511Crossref PubMed Scopus (104) Google Scholar)RECKGDPD5/GDE2GDPD domainEmbryonic lethality(5Park S. Lee C. Sabharwal P. Zhang M. Meyers C.L. Sockanathan S. GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK.Science. 2013; 339: 324-328Crossref PubMed Scopus (59) Google Scholar, 67Oh J. Takahashi R. Kondo S. Mizoguchi A. Adachi E. Sasahara R.M. Nishimura S. Imamura Y. Kitayama H. Alexander D.B. et al.The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.Cell. 2001; 107: 789-800Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar)TEX101ACENot determinedaHas not been reported.Male infertility(6Fujihara Y. Tokuhiro K. Muro Y. Kondoh G. Araki Y. Ikawa M. Okabe M. Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa.Proc. Natl. Acad. Sci. USA. 2013; 110: 8111-8116Crossref PubMed Scopus (0) Google Scholar, 7Kondoh G. Tojo H. Nakatani Y. Komazawa N. Murata C. Yamagata K. Maeda Y. Kinoshita T. Okabe M. Taguchi R. et al.Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization.Nat. Med. 2005; 11: 160-166Crossref PubMed Scopus (179) Google Scholar)IZUMO1R/JUNONot determinedaHas not been reported.Not determinedaHas not been reported.Female infertility(104Bianchi E. Doe B. Goulding D. Wright G.J. Juno is the egg Izumo receptor and is essential for mammalian fertilization.Nature. 2014; 508: 483-487Crossref PubMed Scopus (272) Google Scholar)a Has not been reported. Open table in a new tab A unique feature of GPI-APs is their cleavage by specific phospholipases, resulting in the release of the protein from the cell membrane. Among GPI-specific phospholipases, the only purified and characterized mammalian phospholipase is a GPI-specific phospholipase D (GPI-PLD), GPLD1, which is abundant in serum (9Metz C.N. Brunner G. Choi-Muira N.H. Nguyen H. Gabrilove J. Caras I.W. Altszuler N. Rifkin D.B. Wilson E.L. Davitz M.A. Release of GPI-anchored membrane proteins by a cell-associated GPI-specific phospholipase D.EMBO J. 1994; 13: 1741-1751Crossref PubMed Scopus (119) Google Scholar, 10Low M.G. Prasad A.R. A phospholipase D specific for the phosphatidylinositol anchor of cell-surface proteins is abundant in plasma.Proc. Natl. Acad. Sci. USA. 1988; 85: 980-984Crossref PubMed Google Scholar, 11Davitz M.A. Hereld D. Shak S. Krakow J. Englund P.T. Nussenzweig V. A glycan-phosphatidylinositol-specific phospholipase D in human serum.Science. 1987; 238: 81-84Crossref PubMed Google Scholar). GPLD1 is a soluble protein with two functional domains, an N-terminal catalytic domain and a predicted C-terminal β-propeller domain (12Heller M. Butikofer P. Brodbeck U. Generation by limited proteolysis of a catalytically active 39-kDa protein from the 115-kDa form of phosphatidylinositol-glycan-specific phospholipase D from bovine serum.Eur. J. Biochem. 1994; 224: 823-833Crossref PubMed Google Scholar, 13Springer T.A. Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain.Proc. Natl. Acad. Sci. USA. 1997; 94: 65-72Crossref PubMed Google Scholar). GPLD1 hydrolyzes GPI anchors that have acylated inositol, unlike GPI anchors cleaved by PI-PLC and GPI-PLC (3Ikezawa H. Glycosylphosphatidylinositol (GPI)-anchored proteins.Biol. Pharm. Bull. 2002; 25: 409-417Crossref PubMed Scopus (223) Google Scholar). The catalytic activity of mouse GPLD1 depends on histidines at positions 29, 125, 133, and 158 in the catalytic site (14Raikwar N.S. Bowen R.F. Deeg M.A. Mutating His29, His125, His133 or His158 abolishes glycosylphosphatidylinositol-specific phospholipase D catalytic activity.Biochem. J. 2005; 391: 285-289Crossref PubMed Scopus (6) Google Scholar). Membrane-bound GPI-AP is released from the cell surface by GPLD1 in several important cellular processes, including adhesion, differentiation, proliferation, survival, and oncogenesis. Although the physiological role of GPLD1 is unknown, GPLD1 substrates have been identified, and their roles have been investigated in gene KO mice (Table 1). Plasminogen activator urokinase receptor (PLAUR, also known as CD87 and uPAR) is a GPI-AP receptor that binds to plasminogen activator urokinase (PLAU, also known as uPA) (15Blasi F. Carmeliet P. uPAR: a versatile signalling orchestrator.Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1000) Google Scholar). PLUAR was identified as a multifunctional cell-surface receptor that regulates cellular differentiation, proliferation, migration, adhesion, and invasion (15Blasi F. Carmeliet P. uPAR: a versatile signalling orchestrator.Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1000) Google Scholar, 16Ragno P. The urokinase receptor: a ligand or a receptor? Story of a sociable molecule.Cell. Mol. Life Sci. 2006; 63: 1028-1037Crossref PubMed Scopus (0) Google Scholar). When bound to a PLAU, PLAUR functions as a signaling receptor that converts plasminogen into plasmin, which upon activation triggers an extracellular proteolysis cascade (17Blasi F. Sidenius N. The urokinase receptor: focused cell surface proteolysis, cell adhesion and signaling.FEBS Lett. 2010; 584: 1923-1930Crossref PubMed Scopus (198) Google Scholar). PLAUR also interacts nonproteolytically with vitronectin, an interaction that induces the migration of various cell types. PLAUR activity is regulated by receptor shedding and cleavage. Receptor shedding is mediated by cleavage close to the GPI anchor by GPLD1 and several proteases (18Wilhelm O.G. Wilhelm S. Escott G.M. Lutz V. Magdolen V. Schmitt M. Rifkin D.B. Wilson E.L. Graeff H. Brunner G. Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression.J. Cell. Physiol. 1999; 180: 225-235Crossref PubMed Scopus (124) Google Scholar), whereas receptor cleavages release the N-terminal ligand binding domain (D1) from the other domains (D2D3) (15Blasi F. Carmeliet P. uPAR: a versatile signalling orchestrator.Nat. Rev. Mol. Cell Biol. 2002; 3: 932-943Crossref PubMed Scopus (1000) Google Scholar). These modifications are independent, and the resulting forms of PLAUR have different biological activities. Although minor phenotypes were observed in Pluar KO mice, PLUAR was dispensable for development and fertility in mice (19Bugge T.H. Suh T.T. Flick M.J. Daugherty C.C. Romer J. Solberg H. Ellis V. Dano K. Degen J.L. The receptor for urokinase-type plasminogen activator is not essential for mouse development or fertility.J. Biol. Chem. 1995; 270: 16886-16894Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Carcinoembryonic antigen (CEA), first described in 1965, is a highly glycosylated immunoglobulin-related protein whose serum level increases in some types of cancer (20Goldenberg D.M. Sharkey R.M. Primus F.J. Carcinoembryonic antigen in histopathology: immunoperoxidase staining of conventional tissue sections.J. Natl. Cancer Inst. 1976; 57: 11-22Crossref PubMed Scopus (194) Google Scholar, 21Gold P. Freedman S.O. Specific carcinoembryonic antigens of the human digestive system.J. Exp. Med. 1965; 122: 467-481Crossref PubMed Google Scholar). CEA-related cell-adhesion molecules (CEACAMs) have been implicated in numerous physiological and pathological functions (22Tchoupa A.K. Schuhmacher T. Hauck C.R. Signaling by epithelial members of the CEACAM family - mucosal docking sites for pathogenic bacteria.Cell Commun. Signal. 2014; 12: 27Crossref PubMed Scopus (50) Google Scholar). In humans, there are three major CEACAMs on epithelial tissues: one transmembrane type (CEACAM1) and two GPI-anchored types (CEACAM5 and CEACAM6) (23Kuespert K. Pils S. Hauck C.R. CEACAMs: their role in physiology and pathophysiology.Curr. Opin. Cell Biol. 2006; 18: 565-571Crossref PubMed Scopus (232) Google Scholar). Because Ceacam1 KO mice have no gross abnormalities, epithelial CEACAMs seem to contribute to the fine-tuning of cellular events (24Leung N. Turbide C. Olson M. Marcus V. Jothy S. Beauchemin N. Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis.Oncogene. 2006; 25: 5527-5536Crossref PubMed Scopus (66) Google Scholar). CEACAMs may be more important under pathological conditions, as they are bound by various pathogens (22Tchoupa A.K. Schuhmacher T. Hauck C.R. Signaling by epithelial members of the CEACAM family - mucosal docking sites for pathogenic bacteria.Cell Commun. Signal. 2014; 12: 27Crossref PubMed Scopus (50) Google Scholar). CEACAM5 is released by GPLD1-mediated GPI-anchor cleavage (25Yamamoto Y. Hirakawa E. Mori S. Hamada Y. Kawaguchi N. Matsuura N. Cleavage of carcinoembryonic antigen induces metastatic potential in colorectal carcinoma.Biochem. Biophys. Res. Commun. 2005; 333: 223-229Crossref PubMed Scopus (24) Google Scholar); it is overexpressed in many cancers and is a widely used tumor biomarker (20Goldenberg D.M. Sharkey R.M. Primus F.J. Carcinoembryonic antigen in histopathology: immunoperoxidase staining of conventional tissue sections.J. Natl. Cancer Inst. 1976; 57: 11-22Crossref PubMed Scopus (194) Google Scholar, 21Gold P. Freedman S.O. Specific carcinoembryonic antigens of the human digestive system.J. Exp. Med. 1965; 122: 467-481Crossref PubMed Google Scholar). The analysis of Ceacam5 KO mice has not been reported yet. Protease serine (PRSS)8 (also known as prostasin) is a trypsin-like serine peptidase encoded by the PRSS8 gene. It was purified as a soluble enzyme from human seminal fluid and is highly expressed in kidney, lung, pancreas, and prostate in mice and humans (26Verghese G.M. Tong Z.Y. Bhagwandin V. Caughey G.H. Mouse prostasin gene structure, promoter analysis, and restricted expression in lung and kidney.Am. J. Respir. Cell Mol. Biol. 2004; 30: 519-529Crossref PubMed Scopus (24) Google Scholar, 27Yu J.X. Chao L. Chao J. Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland.J. Biol. Chem. 1994; 269: 18843-18848Abstract Full Text PDF PubMed Google Scholar). As a GPI-AP, PRSS8 can be removed from the cell membrane by treatment with PI-PLC (28Chen L.M. Skinner M.L. Kauffman S.W. Chao J. Chao L. Thaler C.D. Chai K.X. Prostasin is a glycosylphosphatidylinositol-anchored active serine protease.J. Biol. Chem. 2001; 276: 21434-21442Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Under physiological conditions, PRSS8 secretion from the membrane-bound form depends on GPI-anchor cleavage by endogenous GPLD1 in epithelial cells (29Verghese G.M. Gutknecht M.F. Caughey G.H. Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor.Am. J. Physiol. Cell Physiol. 2006; 291: C1258-C1270Crossref PubMed Scopus (55) Google Scholar). PRSS8 and the type II transmembrane serine protease, matriptase/ST14, are generally recognized to interact with serine protease inhibitors (SPINT1 and SPINT2) and are indispensable for epithelial development and homeostasis (30Szabo R. Bugge T.H. Membrane-anchored serine proteases in vertebrate cell and developmental biology.Annu. Rev. Cell Dev. Biol. 2011; 27: 213-235Crossref PubMed Scopus (78) Google Scholar). PRSS8 is required for terminal epidermal differentiation and postnatal survival in mice (31Hummler E. Dousse A. Rieder A. Stehle J.C. Rubera I. Osterheld M.C. Beermann F. Frateschi S. Charles R.P. The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation.PLoS One. 2013; 8: e55796Crossref PubMed Scopus (15) Google Scholar), but its enzymatic activity is not required for development and postnatal homeostasis (32Peters D.E. Szabo R. Friis S. Shylo N.A. Uzzun Sales K. Holmbeck K. Bugge T.H. The membrane-anchored serine protease prostasin (CAP1/PRSS8) supports epidermal development and postnatal homeostasis independent of its enzymatic activity.J. Biol. Chem. 2014; 289: 14740-14749Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Thus, the nonenzymatic activity of PRSS8 is essential for in vivo development. The role of GPLD1-mediated release of PRSS8 in vivo has not been determined. Teratocarcinoma-derived growth factor 1 (TDGF1) is a GPI-AP and a member of the epidermal growth factor-CFC (CRIPTO-1/FRL-1/cryptic) family. TDGF1 interacts with various components of multiple signal pathways to enhance stem cell renewal, epithelial-mesenchymal transition, proliferation, and oncogenesis (33Klauzinska M. Castro N.P. Rangel M.C. Spike B.T. Gray P.C. Bertolette D. Cuttitta F. Salomon D. The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition.Semin. Cancer Biol. 2014; 29: 51-58Crossref PubMed Scopus (57) Google Scholar). TDGF1 acts as both a ligand and coreceptor in the nodal signaling pathway that involves Smad 2, 3, and 4 (34Yan Y.T. Liu J.J. Luo Y. E C. Haltiwanger R.S. Abate-Shen C. Shen M.M. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway.Mol. Cell. Biol. 2002; 22: 4439-4449Crossref PubMed Scopus (159) Google Scholar, 35Whitman M. Nodal signaling in early vertebrate embryos: themes and variations.Dev. Cell. 2001; 1: 605-617Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). GPI-anchored TDGF1 is required for paracrine activity as a nodal coreceptor (36Watanabe K. Hamada S. Bianco C. Mancino M. Nagaoka T. Gonzales M. Bailly V. Strizzi L. Salomon D.S. Requirement of glycosylphosphatidylinositol anchor of Cripto-1 for trans activity as a Nodal co-receptor.J. Biol. Chem. 2007; 282: 35772-35786Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). In its soluble form, TDGF1 functions as a ligand in tumor progression. Because the shedding of TDGF1 is mediated by GPLD1 activity at the GPI-anchor site, soluble TDGF1 may stimulate endothelial cell migration and tumor angiogenesis (37Watanabe K. Bianco C. Strizzi L. Hamada S. Mancino M. Bailly V. Mo W. Wen D. Miatkowski K. Gonzales M. et al.Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration.J. Biol. Chem. 2007; 282: 31643-31655Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). TDGF1 is essential for embryogenesis and cellular transformation in mice (38Ding J. Yang L. Yan Y.T. Chen A. Desai N. Wynshaw-Boris A. Shen M.M. Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo.Nature. 1998; 395: 702-707Crossref PubMed Scopus (375) Google Scholar), but the physiological functions regulated by the membrane-bound and soluble forms have not been determined (34Yan Y.T. Liu J.J. Luo Y. E C. Haltiwanger R.S. Abate-Shen C. Shen M.M. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway.Mol. Cell. Biol. 2002; 22: 4439-4449Crossref PubMed Scopus (159) Google Scholar). Glypicans (GPCs) are heparin sulfate proteoglycans that are bound to the cell surface of the plasma membrane by a GPI anchor (39Filmus J. Capurro M. Rast J. Glypicans.Genome Biol. 2008; 9: 224Crossref PubMed Scopus (342) Google Scholar). Two GPCs, division abnormally delayed (DALLY) and Dally-like protein (DLP), have been identified in Drosophila (40Baeg G.H. Lin X. Khare N. Baumgartner S. Perrimon N. Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless.Development. 2001; 128: 87-94Crossref PubMed Google Scholar, 41Nakato H. Futch T.A. Selleck S.B. The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila.Development. 1995; 121: 3687-3702Crossref PubMed Google Scholar). The six GPC family proteins (GPC1–6) have been conserved in mice and humans (39Filmus J. Capurro M. Rast J. Glypicans.Genome Biol. 2008; 9: 224Crossref PubMed Scopus (342) Google Scholar, 42Jen Y.H. Musacchio M. Lander A.D. Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis.Neural Dev. 2009; 4: 33Crossref PubMed Scopus (64) Google Scholar, 43Aikawa T. Whipple C.A. Lopez M.E. Gunn J. Young A. Lander A.D. Korc M. Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells.J. Clin. Invest. 2008; 118: 89-99Crossref PubMed Scopus (118) Google Scholar, 44Cano-Gauci D.F. Song H.H. Yang H. McKerlie C. Choo B. Shi W. Pullano R. Piscione T.D. Grisaru S. Soon S. et al.Glypican-3-deficient mice exhibit developmental overgrowth and some of the abnormalities typical of Simpson-Golabi-Behmel syndrome.J. Cell Biol. 1999; 146: 255-264Crossref PubMed Scopus (271) Google Scholar). GPCs regulate signaling pathways triggered by Hedgehogs, Wnts, bone morphogenetic proteins, and fibroblast growth factors, and function in axon guidance and excitatory synapses (45Filmus J. Capurro M. The role of glypicans in Hedgehog signaling.Matrix Biol. 2014; 35: 248-252Crossref PubMed Scopus (76) Google Scholar). GPI-anchored GPCs interact directly with Wnt family proteins and can stimulate Wnt signaling by facilitating or stabilizing the interaction between Wnts and their receptors (46Song H.H. Shi W. Xiang Y.Y. Filmus J. The loss of glypican-3 induces alterations in Wnt signaling.J. Biol. Chem. 2005; 280: 2116-2125Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 47Capurro M.I. Xiang Y.Y. Lobe C. Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling.Cancer Res. 2005; 65: 6245-6254Crossref PubMed Scopus (344) Google Scholar, 48Ohkawara B. Yamamoto T.S. Tada M. Ueno N. Role of glypican 4 in the regulation of convergent extension movements during gastrulation in Xenopus laevis.Development. 2003; 130: 2129-2138Crossref PubMed Scopus (143) Google Scholar, 49De Cat B. Muyldermans S.Y. Coomans C. Degeest G. Vanderschueren B. Creemers J. Biemar F. Peers B. David G. Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements.J. Cell Biol. 2003; 163: 625-635Crossref PubMed Scopus (131) Google Scholar, 50Ai X. Do A.T. Lozynska O. Kusche-Gullberg M. Lindahl U. Emerson Jr, C.P. QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling.J. Cell Biol. 2003; 162: 341-351Crossref PubMed Scopus (332) Google Scholar). GPCs may also inhibit Wnt signaling (47Capurro M.I. Xiang Y.Y. Lobe C. Filmus J. Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling.Cancer Res. 2005; 65: 6245-6254Crossref PubMed Scopus (344) Google Scholar). Moreover, in Drosophila, secreted GPCs have been reported to play a role in the transport of Wnts in the imaginal wing discs for regulation of morphogen gradient formation during development (51Yan D. Lin X. Shaping morphogen gradients by proteoglycans.Cold Spring Harb. Perspect. Biol. 2009; 1: a002493Crossref PubMed Scopus (208) Google Scholar, 52Han C. Yan D. Belenkaya T.Y. Lin X. Drosophila glypicans Dally and Dally-like shape the extracellular Wingless morphogen gradient in the wing disc.Development. 2005; 132: 667-679Crossref PubMed Scopus (156) Google Scholar, 53Franch-Marro X. Marchand O. Piddini E. Ricardo S. Alexandre C. Vincent J.P. Glypicans shunt the Wingless signal between local signalling and further transport.Development. 2005; 132: 659-666Crossref PubMed Scopus (99) Google Scholar, 54Kirkpatrick C.A. Dimitroff B.D. Rawson J.M. Selleck S.B. Spatial regulation of Wingless morphogen distribution and signaling by Dally-like protein.Dev. Cell. 2004; 7: 513-523Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). NOTUM, a member of the α/β-hydrolase superfamily, regulates Wnt activity by modifying the heparin sulfate chains of GPCs, DALLY, and DLP (55Giráldez A.J. Copley R.R. Cohen S.M. HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient.Dev. Cell. 2002; 2: 667-676Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). NOTUM was reported to induce shedding of DLP from the cell surface by cleaving its GPI anchor (8Kreuger J. Perez L. Giraldez A.J. Cohen S.M. Opposing activities of Dally-like glypican at high and low levels of Wingless morphogen activity.Dev. Cell. 2004; 7: 503-512Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar) (Table 1). However, the idea that NOTUM mediates release of GPCs was called into question by a report that recombinant Drosophila NOTUM cannot cleave DLP and instead functions as a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins (56Kakugawa S. Langton P.F. Zebisch M. Howell S.A. Chang T.H. Liu Y. Feizi T. Bineva G. O'Reilly N. Snijders A.P. et al.Notum deacylates Wnt proteins to suppress signalling activity.Nature. 2015; 519: 187-192Crossref PubMed Scopus (182) Google Scholar). Xenopus NOTUM is also a Wnt deacylase and is required for brain development (57Zhang X. Cheong S.M. Amado N.G. Reis A.H. MacDonald B.T. Zebisch M. Jones E.Y. Abreu J.G. He X. Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation.Dev. Cell. 2015; 32: 719-730Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). Mammalian NOTUM was reported to cleave not only GPCs (GPC3, GPC5, and GPC6), but also other GPI-APs (PLAUR and T-cadherin) (58Traister A. Shi W. Filmus J. Mammalian Notum induces the release of glypicans and other GPI-anchored proteins from the cell surface.Biochem. J. 2008; 410: 503-511Crossref PubMed Scopus (104) Google Scholar). Further study is needed to resolve questions about the function of NOTUM and its enzymatic activities. Glycerophosphodiester phosphodiesterases (GDPDs) are periplasmic and cytosolic proteins that are critical for the hydrolysis of deacylated glycerophospholipids to glycerol phosphate and alcohol, which are then utilized as a major source of carbon and phosphate (59Yanaka N. Mammalian glycerophosphodiester phosphodiesterases.Biosci. Biotechnol. Biochem. 2007; 71: 1811-1818Crossref PubMed Scopus (45) Google Scholar). Though
Referência(s)