Abstract
In this paper, we show that the pH optimum for the plasma membrane (PM)-associated activity of four glycohydrolases (conduritol B epoxide sensitive β-glucosidase, β-glucosidase GBA2, β-hexosaminidase and β-galactosidase) measured on intact cells is acidic. Moreover, we show that drugs able to modify the efflux of protons across the PM, thus locally affecting the extracellular proton concentration close to the PM, are able to modulate the activities of these enzymes. These data strongly suggest that pH-dependent modulation of PM-associated glycohydrolases activities could be an effective way to locally modulate the cell surface glycoconjugate composition.
Similar content being viewed by others
References
Hakomori S (1996) Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res 56:5309–5318
Hakomori S (2002) Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci USA 99:10231–10233
Dennis JW, Granovsky M, Warren CE (1999) Glycoprotein glycosylation and cancer progression. Biochim Biophys Acta 1473:21–34
Traylor TD, Hogan EL (1980) Gangliosides of human cerebral astrocytomas. J Neurochem 34:126–131
Jennemann R, Rodden A, Bauer BL, Mennel HD et al (1990) Glycosphingolipids of human gliomas. Cancer Res 50:7444–7449
Shinoura N, Dohi T, Kondo T, Yoshioka M et al (1992) Ganglioside composition and its relation to clinical data in brain tumors. Neurosurgery 31:541–549
Pan XL, Izumi T, Yamada H, Akiyoshi K et al (2000) Ganglioside patterns in neuroepithelial tumors of childhood. Brain Dev 22:196–198
Wikstrand CJ, He XM, Fuller GN, Bigner SH et al (1991) Occurrence of lacto series gangliosides 3′-isoLM1 and 3′,6′-isoLD1 in human gliomas in vitro and in vivo. J Neuropathol Exp Neurol 50:756–769
Moskal JR, Kroes RA, Dawson G (2009) The glycobiology of brain tumors: disease relevance and therapeutic potential. Expert Rev Neurother 9:1529–1545
Meany DL, Chan DW (2011) Aberrant glycosylation associated with enzymes as cancer biomarkers. Clin Proteomics 8:7
Guo HB, Lee I, Kamar M, Pierce M (2003) N-acetylglucosaminyltransferase V expression levels regulate cadherin-associated homotypic cell–cell adhesion and intracellular signaling pathways. J Biol Chem 278:52412–52424
Takahashi M, Kuroki Y, Ohtsubo K, Taniguchi N (2009) Core fucose and bisecting GlcNAc, the direct modifiers of the N-glycan core: their functions and target proteins. Carbohydr Res 344:1387–1390
Dennis JW, Laferte S, Waghorne C, Breitman ML et al (1987) Beta 1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 236:582–585
Yamamoto H, Swoger J, Greene S, Saito T et al (2000) Beta1,6-N-acetylglucosamine-bearing N-glycans in human gliomas: implications for a role in regulating invasivity. Cancer Res 60:134–142
Yamamoto H, Oviedo A, Sweeley C, Saito T et al (2001) Alpha2,6-sialylation of cell-surface N-glycans inhibits glioma formation in vivo. Cancer Res 61:6822–6829
Kroes RA, He H, Emmett MR, Nilsson CL et al (2010) Overexpression of ST6GalNAcV, a ganglioside-specific alpha2,6-sialyltransferase, inhibits glioma growth in vivo. Proc Natl Acad Sci USA 107:12646–12651
Prinetti A, Chigorno V, Mauri L, Loberto N et al (2007) Modulation of cell functions by glycosphingolipid metabolic remodeling in the plasma membrane. J Neurochem 103(Suppl 1):113–125
Aureli M, Loberto N, Chigorno V, Prinetti A et al (2011) Remodeling of sphingolipids by plasma membrane associated enzymes. Neurochem Res 36:1636–1644
Valaperta R, Chigorno V, Basso L, Prinetti A et al (2006) Plasma membrane production of ceramide from ganglioside GM3 in human fibroblasts. FASEB J 20:1227–1229
Aureli M, Loberto N, Lanteri P, Chigorno V et al (2011) Cell surface sphingolipid glycohydrolases in neuronal differentiation and aging in culture. J Neurochem 116:891–899
Miyagi T, Wada T, Yamaguchi K (2008) Roles of plasma membrane-associated sialidase NEU3 in human cancers. Biochim Biophys Acta 1780:532–537
Kakugawa Y, Wada T, Yamaguchi K, Yamanami H et al (2002) Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression. Proc Natl Acad Sci USA 99:10718–10723
Wada T, Hata K, Yamaguchi K, Shiozaki K et al (2007) A crucial role of plasma membrane-associated sialidase in the survival of human cancer cells. Oncogene 26:2483–2490
Boot RG, Verhoek M, Donker-Koopman W, Strijland A et al (2007) Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J Biol Chem 282:1305–1312
Mencarelli S, Cavalieri C, Magini A, Tancini B et al (2005) Identification of plasma membrane associated mature beta-hexosaminidase A, active towards GM2 ganglioside, in human fibroblasts. FEBS Lett 579:5501–5506
Aureli M, Masilamani AP, Illuzzi G, Loberto N et al (2009) Activity of plasma membrane beta-galactosidase and beta-glucosidase. FEBS Lett 583:2469–2473
Monti E, Bassi MT, Papini N, Riboni M et al (2000) Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane. Biochem J 349:343–351
van Weely S, Brandsma M, Strijland A, Tager JM et al (1993) Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease. Biochim Biophys Acta 1181:55–62
Wakabayashi S, Shigekawa M, Pouyssegur J (1997) Molecular physiology of vertebrate Na+/H+ exchangers. Physiol Rev 77:51–74
Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299
Chiche J, Brahimi-Horn MC, Pouyssegur J (2010) Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14:771–794
Cardone RA, Casavola V, Reshkin SJ (2005) The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 5:786–795
Izumi H, Torigoe T, Ishiguchi H, Uramoto H et al (2003) Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev 29:541–549
Stock C, Gassner B, Hauck CR, Arnold H et al (2005) Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange. J Physiol 567:225–238
Reshkin SJ, Bellizzi A, Albarani V, Guerra L et al (2000) Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na(+)/H(+) exchange, motility, and invasion induced by serum deprivation. J Biol Chem 275:5361–5369
Overkleeft HS, Renkema GH, Neele J, Vianello P et al (1998) Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem 273:26522–26527
Leroy JG, Ho MW, MacBrinn MC, Zielke K et al (1972) I-cell disease: biochemical studies. Pediatr Res 6:752–757
Chiche J, Ilc K, Laferriere J, Trottier E et al (2009) Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res 69:358–368
Thongon N, Krishnamra N (2011) Omeprazole decreases magnesium transport across Caco-2 monolayers. World J Gastroenterol 17:1574–1583
Wong P, Kleemann HW, Tannock IF (2002) Cytostatic potential of novel agents that inhibit the regulation of intracellular pH. Br J Cancer 87:238–245
Elliott JT, Tona A, Plant AL (2003) Comparison of reagents for shape analysis of fixed cells by automated fluorescence microscopy. Cytometry A 52:90–100
Yuanbo C, Fan Z, Jiachang Y (2005) Detecting proton flux across chromatophores driven by F0F1-ATPase using N-(fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoeth anolamine, triethylammonium salt. Anal Biochem 344:102–107
Stock C, Mueller M, Kraehling H, Mally S et al (2007) pH nanoenvironment at the surface of single melanoma cells. Cell Physiol Biochem 20:679–686
Krahling H, Mally S, Eble JA, Noel J et al (2009) The glycocalyx maintains a cell surface pH nanoenvironment crucial for integrin-mediated migration of human melanoma cells. Pflugers Arch 458:1069–1083
Reber F, Gersch U, Funk RW (2003) Blockers of carbonic anhydrase can cause increase of retinal capillary diameter, decrease of extracellular and increase of intracellular pH in rat retinal organ culture. Graefes Arch Clin Exp Ophthalmol 241:140–148
Svastova E, Hulikova A, Rafajova M, Zat’ovicova M et al (2004) Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 577:439–445
Cinar A, Chen M, Riederer B, Bachmann O et al (2007) NHE3 inhibition by cAMP and Ca2+ is abolished in PDZ-domain protein PDZK1-deficient murine enterocytes. J Physiol 581:1235–1246
Zhdanov AV, Ward MW, Taylor CT, Souslova EA et al (2010) Extracellular calcium depletion transiently elevates oxygen consumption in neurosecretory PC12 cells through activation of mitochondrial Na+/Ca2+ exchange. Biochim Biophys Acta 1797:1627–1637
Putney LK, Denker SP, Barber DL (2002) The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu Rev Pharmacol Toxicol 42:527–552
Wakabayashi S, Hisamitsu T, Pang T, Shigekawa M (2003) Kinetic dissection of two distinct proton binding sites in Na+/H+ exchangers by measurement of reverse mode reaction. J Biol Chem 278:43580–43585
Olbe L, Carlsson E, Lindberg P (2003) A proton-pump inhibitor expedition: the case histories of omeprazole and esomeprazole. Nat Rev Drug Discov 2:132–139
Miyagi T, Wada T, Yamaguchi K, Hata K et al (2008) Plasma membrane-associated sialidase as a crucial regulator of transmembrane signalling. J Biochem 144:279–285
Preti A, Fiorilli A, Lombardo A, Caimi L et al (1980) Occurrence of sialyltransferase activity in the synaptosomal membranes prepared from calf brain cortex. J Neurochem 35:281–296
Crespo PM, Demichelis VT, Daniotti JL (2010) Neobiosynthesis of glycosphingolipids by plasma membrane-associated glycosyltransferases. J Biol Chem 285:29179–29190
Alessenko AV (2000) The role of sphingomyelin cycle metabolites in transduction of signals of cell proliferation, differentiation and death. Membr Cell Biol 13:303–320
van Blitterswijk WJ, van der Luit AH, Veldman RJ, Verheij M et al (2003) Ceramide: second messenger or modulator of membrane structure and dynamics? Biochem J 369:199–211
Miyagi T, Wada T, Iwamatsu A, Hata K et al (1999) Molecular cloning and characterization of a plasma membrane-associated sialidase specific for gangliosides. J Biol Chem 274:5004–5011
Reddy A, Caler EV, Andrews NW (2001) Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106:157–169
Stuwe L, Muller M, Fabian A, Waning J et al (2007) pH dependence of melanoma cell migration: protons extruded by NHE1 dominate protons of the bulk solution. J Physiol 585:351–360
Bourguignon LY, Singleton PA, Diedrich F, Stern R et al (2004) CD44 interaction with Na+–H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J Biol Chem 279:26991–27007
Kalka D, von Reitzenstein C, Kopitz J, Cantz M (2001) The plasma membrane ganglioside sialidase cofractionates with markers of lipid rafts. Biochem Biophys Res Commun 283:989–993
Wang Y, Yamaguchi K, Wada T, Hata K et al (2002) A close association of the ganglioside-specific sialidase Neu3 with caveolin in membrane microdomains. J Biol Chem 277:26252–26259
Willoughby D, Masada N, Crossthwaite AJ, Ciruela A et al (2005) Localized Na+/H+ exchanger 1 expression protects Ca2+-regulated adenylyl cyclases from changes in intracellular pH. J Biol Chem 280:30864–30872
Prinetti A, Loberto N, Chigorno V, Sonnino S (2009) Glycosphingolipid behaviour in complex membranes. Biochim Biophys Acta 1788:184–193
Acknowledgments
This work was supported by grant PRIN (Italy) to S.S.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Special Issue: In Honor of Bob Leeden.
Rights and permissions
About this article
Cite this article
Aureli, M., Loberto, N., Bassi, R. et al. Plasma Membrane-Associated Glycohydrolases Activation by Extracellular Acidification due to Proton Exchangers. Neurochem Res 37, 1296–1307 (2012). https://doi.org/10.1007/s11064-012-0725-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-012-0725-1