Skip to main content
SpringerLink
Log in

GLIALCAM, A Glial Cell Adhesion Molecule Implicated in Neurological Disease

  • Chapter
  • First Online:
Cell Adhesion Molecules

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 8))

Abstract

GlialCAM (also named HepaCAM) is a cell adhesion molecule expressed mainly in glial cells from the central nervous system and the liver. GlialCAM plays different roles according to its cellular context. In epithelial cell lines, overexpression of GlialCAM increases cell adhesion and motility but also inhibits cell growth in tumor cell lines, leading to senescence. In glial cells, however, its function is quite different. GlialCAM acts a regulator of subcellular traffic of MLC1, a protein with unknown function involved in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare neurological condition. Moreover, GlialCAM itself has been found to be responsible for some of the cases of this disease. Additionally, GlialCAM also works as an auxiliary subunit of the chloride channel ClC-2, regulating its targeting to cell–cell junctions and modifying its functional properties. In summary, GlialCAM has different functions not only related to its adhesive nature, and defects in these functions lead to neurological disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Allaman I, Belanger M, Magistretti PJ (2011) Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 34:76–87

    Article  CAS  PubMed  Google Scholar 

  • Ambrosini E, Serafini B, Lanciotti A, Tosini F, Scialpi F, Psaila R, Raggi C, Di Girolamo F, Petrucci TC, Aloisi F (2008) Biochemical characterization of MLC1 protein in astrocytes and its association with the dystrophin-glycoprotein complex. Mol Cell Neurosci 37:480–493

    Article  CAS  PubMed  Google Scholar 

  • Arcangeli A, Becchetti A (2006) Complex functional interaction between integrin receptors and ion channels. Trends Cell Biol 16:631–639

    Article  CAS  PubMed  Google Scholar 

  • Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738

    Article  CAS  PubMed  Google Scholar 

  • Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, Jentsch TJ (2007) Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci 27:6581–6589

    Article  CAS  PubMed  Google Scholar 

  • Boor I, Nagtegaal M, Kamphorst W, van der Valk P, Pronk JC, van Horssen J, Dinopoulos A, Bove KE, Pascual-Castroviejo I, Muntoni F et al (2007) MLC1 is associated with the dystrophin-glycoprotein complex at astrocytic endfeet. Acta Neuropathol 114:403–410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brackenbury WJ, Isom LL (2010) Na channel beta subunits: overachievers of the Ion channel family. Front Pharmacol 2:53

    Google Scholar 

  • Capdevila-Nortes X, Lopez-Hernandez T, Apaja PM, Lopez de Heredia M, Sirisi S, Callejo G, Arnedo T, Nunes V, Lukacs GL, Gasull X et al (2013). Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet 22(21):4405–4416. doi:10.1093/hmg/ddt290

    Google Scholar 

  • Chen Y, Aulia S, Li L, Tang BL (2006) AMIGO and friends: an emerging family of brain-enriched, neuronal growth modulating, type I transmembrane proteins with leucine-rich repeats (LRR) and cell adhesion molecule motifs. Brain Res Rev 51:265–274

    Article  CAS  PubMed  Google Scholar 

  • Chung Moh M, Hoon Lee L, Shen S (2005) Cloning and characterization of hepaCAM, a novel Ig-like cell adhesion molecule suppressed in human hepatocellular carcinoma. J Hepatol 42:833–841

    Article  PubMed  Google Scholar 

  • Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, van Berkel C, Polder E, Tollard E, Darios F et al (2013) Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol 12:659–668

    Google Scholar 

  • Duarri A, Teijido O, Lopez-Hernandez T, Scheper GC, Barriere H, Boor I, Aguado F, Zorzano A, Palacin M, Martinez A et al (2008) Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects. Hum Mol Genet 17:3728–3739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Duarri A, Lopez de Heredia M, Capdevila-Nortes X, Ridder MC, Montolio M, Lopez-Hernandez T, Boor I, Lien CF, Hagemann T, Messing A et al (2011) Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model. Neurobiol Dis 43:228–238

    Article  CAS  PubMed  Google Scholar 

  • Favre-Kontula L, Rolland A, Bernasconi L, Karmirantzou M, Power C, Antonsson B, Boschert U (2008a) GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. Glia 56:633–645

    Article  PubMed  Google Scholar 

  • Favre-Kontula L, Sattonnet-Roche P, Magnenat E, Proudfoot AE, Boschert U, Xenarios I, Vilbois F, Antonsson B (2008b) Detection and identification of plasma proteins that bind GlialCAM using ProteinChip arrays, SELDI-TOF MS, and nano-LC MS/MS. Proteomics 8:378–388

    Article  CAS  PubMed  Google Scholar 

  • Gaudry JP, Arod C, Sauvage C, Busso S, Dupraz P, Pankiewicz R, Antonsson B (2008) Purification of the extracellular domain of the membrane protein GlialCAM expressed in HEK and CHO cells and comparison of the glycosylation. Protein Expr Purif 58:94–102

    Article  CAS  PubMed  Google Scholar 

  • Ilja Boor PK, de Groot K, Mejaski-Bosnjak V, Brenner C, van der Knaap MS, Scheper GC, Pronk JC (2006) Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis of MLC1. Hum Mutat 27:505–512

    Article  CAS  PubMed  Google Scholar 

  • Jeworutzki E, Lopez-Hernandez T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Muller CS, Schulte U et al (2012) GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(-) channel auxiliary subunit. Neuron 73:951–961

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee LH, Moh MC, Zhang T, Shen S (2009) The immunoglobulin-like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373-MG cells. J Cell Biochem 107:1129–1138

    Article  CAS  PubMed  Google Scholar 

  • Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Konst AA, Boor PK, Mejaski-Bosnjak V, van der Maarel SM, Frants RR, Oudejans CB et al (2001) Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 68:831–838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leegwater PA, Boor PK, Yuan BQ, van der Steen J, Visser A, Konst AA, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS (2002) Identification of novel mutations in MLC1 responsible for megalencephalic leukoencephalopathy with subcortical cysts. Hum Genet 110:279–283

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Hernandez T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S, Duarri A, Schulte U, Fakler B, Nunes V et al (2011a) Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet 88:422–432

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lopez-Hernandez T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernandez-Duenas V, Scheper GC, van der Knaap MS, Casquero P, Ciruela F, Ferrer I et al (2011b) Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet 20:3266–3277

    Article  CAS  PubMed  Google Scholar 

  • Moh MC, Lee LH, Yang X, Shen S (2003) HEPN1, a novel gene that is frequently down-regulated in hepatocellular carcinoma, suppresses cell growth and induces apoptosis in HepG2 cells. J Hepatol 39:580–586

    Article  CAS  PubMed  Google Scholar 

  • Moh MC, Zhang C, Luo C, Lee LH, Shen S (2005) Structural and functional analyses of a novel ig-like cell adhesion molecule, hepaCAM, in the human breast carcinoma MCF7 cells. J Biol Chem 280:27366–27374

    Article  CAS  PubMed  Google Scholar 

  • Moh MC, Zhang T, Lee LH, Shen S (2008) Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells. Carcinogenesis 29:2298–2305

    Article  CAS  PubMed  Google Scholar 

  • Moh MC, Lee LH, Zhang T, Shen S (2009a) Interaction of the immunoglobulin-like cell adhesion molecule hepaCAM with caveolin-1. Biochem Biophys Res Commun 378:755–760

    Article  CAS  PubMed  Google Scholar 

  • Moh MC, Tian Q, Zhang T, Lee LH, Shen S (2009b) The immunoglobulin-like cell adhesion molecule hepaCAM modulates cell adhesion and motility through direct interaction with the actin cytoskeleton. J Cell Physiol 219:382–391

    Article  CAS  PubMed  Google Scholar 

  • Molofsky AV, Krencik R, Ullian EM, Tsai HH, Deneen B, Richardson WD, Barres BA, Rowitch DH (2012) Astrocytes and disease: a neurodevelopmental perspective. Genes Dev 26:891–907

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Montagna G, Teijido O, Eymard-Pierre E, Muraki K, Cohen B, Loizzo A, Grosso P, Tedeschi G, Palacin M, Boespflug-Tanguy O et al (2006) Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. Hum Mutat 27:292

    Article  PubMed  Google Scholar 

  • Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T et al (2012) Glial cells in (patho)physiology. J Neurochem 121:4–27

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Peltola MA, Kuja-Panula J, Lauri SE, Taira T, Rauvala H (2011) AMIGO is an auxiliary subunit of the Kv2.1 potassium channel. EMBO Rep 12:1293–1299

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Piaton G, Gould RM, Lubetzki C (2010) Axon-oligodendrocyte interactions during developmental myelination, demyelination and repair. J Neurochem 114:1243–1260

    CAS  PubMed  Google Scholar 

  • Rash JE (2010) Molecular disruptions of the panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinating diseases of the central nervous system. Neuroscience 168:982–1008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ridder MC, Boor I, Lodder JC, Postma NL, Capdevila-Nortes X, Duarri A, Brussaard AB, Estevez R, Scheper GC, Mansvelder HD et al (2011) Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation. Brain 134:3342–3354

    Article  PubMed  Google Scholar 

  • Scheper GC, van Berkel CG, Leisle L, de Groot KE, Errami A, Jentsch TJ, Van der Knaap MS (2010) Analysis of CLCN2 as candidate gene for megalencephalic leukoencephalopathy with subcortical cysts. Genet Test Mol Biomarkers 14:255–257

    Article  CAS  PubMed  Google Scholar 

  • Spiegel I, Adamsky K, Eisenbach M, Eshed Y, Spiegel A, Mirsky R, Scherer SS, Peles E (2006) Identification of novel cell-adhesion molecules in peripheral nerves using a signal-sequence trap. Neuron Glia Biol 2:27–38

    Article  PubMed Central  PubMed  Google Scholar 

  • Teijido O, Martinez A, Pusch M, Zorzano A, Soriano E, Del Rio JA, Palacin M, Estevez R (2004) Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet 13:2581–2594

    Article  CAS  PubMed  Google Scholar 

  • Teijido O, Casaroli-Marano R, Kharkovets T, Aguado F, Zorzano A, Palacin M, Soriano E, Martinez A, Estevez R (2007) Expression patterns of MLC1 protein in the central and peripheral nervous systems. Neurobiol Dis 26:532–545

    Article  CAS  PubMed  Google Scholar 

  • Thiemann A, Grunder S, Pusch M, Jentsch TJ (1992) A chloride channel widely expressed in epithelial and non-epithelial cells. Nature 356:57–60

    Article  CAS  PubMed  Google Scholar 

  • van der Knaap MS, Barth PG, Stroink H, van Nieuwenhuizen O, Arts WF, Hoogenraad F, Valk J (1995a) Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 37:324–334

    Article  PubMed  Google Scholar 

  • van der Knaap MS, Valk J, Barth PG, Smit LM, van Engelen BG, Tortori Donati P (1995b) Leukoencephalopathy with swelling in children and adolescents: MRI patterns and differential diagnosis. Neuroradiology 37:679–686

    Article  PubMed  Google Scholar 

  • van der Knaap MS, Barth PG, Vrensen GF, Valk J (1996) Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol 92:206–212

    Article  PubMed  Google Scholar 

  • van der Knaap MS, Lai V, Kohler W, Salih MA, Fonseca MJ, Benke TA, Wilson C, Jayakar P, Aine MR, Dom L et al (2010) Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol 67:834–837

    PubMed  Google Scholar 

  • van der Knaap MS, Boor I, Estevez R (2012) Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter edema due to a defect in brain ion and water homeostasis. Lancet Neurol 11(11):973–985

    Article  PubMed  Google Scholar 

  • Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20:588–594

    Article  CAS  PubMed  Google Scholar 

  • Zhang T, Moh MC, Lee LH, Shen S (2010) The immunoglobulin-like cell adhesion molecule hepaCAM is cleaved in the human breast carcinoma MCF7 cells. Int J Oncol 37:155–165

    Article  CAS  PubMed  Google Scholar 

  • Zhang QL, Luo CL, Wu XH, Wang CY, Xu X, Zhang YY, Liu Q, Shen SL (2011) HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma. J Cell Biochem 112:2910–2919

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all members of the lab and to our collaborators for their support. Studies in our lab are supported by SAF 2009-07014, PS09/02672-ERARE, ELA Foundation 2009-017C4 project, 2009 SGR 719, and an ICREA Academia prize.

Compliance with Ethics Requirements

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Physiology Section, Department of Physiological Sciences II, School of Medicine, University of Barcelona, Av. Feixa Llarga s/n, 08907, Barcelona, Spain

    Alejandro Barrallo-Gimeno Ph.D. & Raúl Estévez Ph.D.

Authors
  1. Alejandro Barrallo-Gimeno Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raúl Estévez Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raúl Estévez Ph.D. .

Editor information

Editors and Affiliations

  1. Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Vladimir Berezin

  2. Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Peter S. Walmod

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Barrallo-Gimeno, A., Estévez, R. (2014). GLIALCAM, A Glial Cell Adhesion Molecule Implicated in Neurological Disease. In: Berezin, V., Walmod, P. (eds) Cell Adhesion Molecules. Advances in Neurobiology, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8090-7_3

Download citation

Publish with us

Policies and ethics

Search

Navigation