CD82 Blocks cMet Activation and Overcomes Hepatocyte Growth Factor Effects on Oligodendrocyte Precursor Differentiation

Mechanisms that regulate oligodendrocyte (OL) precursor migration and differentiation are important in normal development and in demyelinating/remyelinating conditions. We previously found that the tetraspanin CD82 is far more highly expressed in O4+ OL precursors of the adult rat brain than those of the neonatal brain. CD82 has been physically linked to cMet, the hepatocyte growth factor (HGF) receptor, in tumor cells, and this interaction decreases downstream signaling. We show here that CD82 inhibits the HGF activation of cMet in neonatal and adult rat OL precursors. CD82 expression is sufficient to allow precursor differentiation into mature OLs even in the presence of HGF. In contrast, CD82 downregulation in adult O4+/CD82+ cells inhibits their differentiation, decreases their accumulation of myelin proteins, and causes a reversion to less mature stages. CD82 expression in neonatal O4+/CD82− cells also blocks Rac1 activation, suggesting a possible regulatory effect on cytoskeletal organization and mobility. Thus, CD82 is a negative regulator of HGF/cMet during OL development and overcomes HGF inhibitory regulation of OL precursor maturation.

[1]  S. Sadiq,et al.  Cerebrospinal hepatocyte growth factor levels correlate negatively with disease activity in multiple sclerosis , 2012, Journal of Neuroimmunology.

[2]  Arnold I Caplan,et al.  Hepatocyte growth factor mediates mesenchymal stem cell–induced recovery in multiple sclerosis models , 2012, Nature Neuroscience.

[3]  C. ffrench-Constant,et al.  Edinburgh Research Explorer Translation of myelin basic protein mRNA in oligodendrocytes is regulated by integrin activation and hnRNP-K , 2022 .

[4]  A. Fontana,et al.  Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis , 2009, Glia.

[5]  M. Assanah,et al.  PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain , 2009, Glia.

[6]  Angeliki Mela,et al.  Neonatal and adult O4+ oligodendrocyte lineage cells display different growth factor responses and different gene expression patterns , 2009, Journal of neuroscience research.

[7]  Angeliki Mela,et al.  The Tetraspanin KAI1/CD82 Is Expressed by Late-Lineage Oligodendrocyte Precursors and May Function to Restrict Precursor Migration and Promote Oligodendrocyte Differentiation and Myelination , 2009, The Journal of Neuroscience.

[8]  Claudia S. Barros,et al.  β1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth , 2009, Development.

[9]  Pat Levitt,et al.  Dynamic gene and protein expression patterns of the autism‐associated met receptor tyrosine kinase in the developing mouse forebrain , 2009, The Journal of comparative neurology.

[10]  C. Miranti.  Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. , 2009, Cellular signalling.

[11]  U. Suter,et al.  The function of RhoGTPases in axon ensheathment and myelination , 2008, Glia.

[12]  K. Shirasuna,et al.  Regulation of c‐Met signaling by the tetraspanin KAI‐1/CD82 affects cancer cell migration , 2007, International journal of cancer.

[13]  H. Okano,et al.  Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury , 2007, Journal of neuroscience research.

[14]  Toshikazu Nakamura,et al.  Hepatocyte growth factor (HGF) promotes oligodendrocyte progenitor cell proliferation and inhibits its differentiation during postnatal development in the rat , 2007, Brain Research.

[15]  J. Ries,et al.  Rho Regulates Membrane Transport in the Endocytic Pathway to Control Plasma Membrane Specialization in Oligodendroglial Cells , 2007, The Journal of Neuroscience.

[16]  K. Handa,et al.  Ganglioside GM2-Tetraspanin CD82 Complex Inhibits Met and Its Cross-talk with Integrins, Providing a Basis for Control of Cell Motility through Glycosynapse* , 2007, Journal of Biological Chemistry.

[17]  Lei Wang,et al.  Cell type-specific functions of Rho GTPases revealed by gene targeting in mice. , 2007, Trends in cell biology.

[18]  K. Nave,et al.  Cdc42 and Rac1 Signaling Are Both Required for and Act Synergistically in the Correct Formation of Myelin Sheaths in the CNS , 2006, The Journal of Neuroscience.

[19]  Xin A. Zhang,et al.  KAI1/CD82, a tumor metastasis suppressor. , 2006, Cancer letters.

[20]  M. Assanah,et al.  Glial Progenitors in Adult White Matter Are Driven to Form Malignant Gliomas by Platelet-Derived Growth Factor-Expressing Retroviruses , 2006, The Journal of Neuroscience.

[21]  B. Trapp,et al.  LINGO-1 negatively regulates myelination by oligodendrocytes , 2005, Nature Neuroscience.

[22]  B. Trapp,et al.  βIV tubulin is selectively expressed by oligodendrocytes in the central nervous system , 2005 .

[23]  P. Jackson,et al.  KAI1 tetraspanin and metastasis suppressor. , 2005, The international journal of biochemistry & cell biology.

[24]  Dino P. Leone,et al.  TGF‐β‐treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF‐c‐Met pathway , 2005, European journal of immunology.

[25]  B. Trapp,et al.  Beta IV tubulin is selectively expressed by oligodendrocytes in the central nervous system. , 2005, Glia.

[26]  G. Bismuth,et al.  Tetraspanin CD82 controls the association of cholesterol-dependent microdomains with the actin cytoskeleton in T lymphocytes: relevance to co-stimulation , 2004, Journal of Cell Science.

[27]  M. Resh,et al.  Signaling from Integrins to Fyn to Rho Family GTPases Regulates Morphologic Differentiation of Oligodendrocytes , 2004, The Journal of Neuroscience.

[28]  C. ffrench-Constant,et al.  Lipid rafts: microenvironments for integrin-growth factor interactions in neural development. , 2004, Biochemical Society transactions.

[29]  J. Goldman,et al.  Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. , 2004, The American journal of pathology.

[30]  C. ffrench-Constant,et al.  Lipid Rafts and Integrin Activation Regulate Oligodendrocyte Survival , 2004, The Journal of Neuroscience.

[31]  E. Odintsova,et al.  Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR , 2003, Journal of Cell Science.

[32]  C. ffrench-Constant,et al.  Regulation of Integrin Growth Factor Interactions in Oligodendrocytes by Lipid Raft Microdomains , 2003, Current Biology.

[33]  S. Rivkees,et al.  Hepatocyte growth factor stimulates the proliferation and migration of oligodendrocyte precursor cells , 2002, Journal of neuroscience research.

[34]  H. Akatsu,et al.  Hepatocyte growth factor in cerebrospinal fluid in neurologic disease , 2002, Acta neurologica Scandinavica.

[35]  J. Goldman,et al.  A2B5+ and O4+ Cycling Progenitors in the Adult Forebrain White Matter Respond Differentially to PDGF-AA, FGF-2, and IGF-1 , 2002, Molecular and Cellular Neuroscience.

[36]  Careen K. Tang,et al.  Overexpression of KAI1 suppresses in vitro invasiveness and in vivo metastasis in breast cancer cells. , 2001, Cancer research.

[37]  W. Richardson,et al.  Control of progenitor cell number by mitogen supply and demand , 2001, Current Biology.

[38]  J. Settleman,et al.  Rho family GTPases: more than simple switches. , 2000, Trends in cell biology.

[39]  H. Hamada,et al.  Overexpression of CD82 on human T cells enhances LFA‐1 / ICAM‐1‐mediated cell‐cell adhesion: functional association between CD82 and LFA‐1 in T cell activation , 1999, European journal of immunology.

[40]  K. Handa,et al.  Motility inhibition and apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9, with concurrent glycosylation. , 1999, Cancer research.

[41]  C. Hubeau,et al.  Signaling through the tetraspanin CD82 triggers its association with the cytoskeleton leading to sustained morphological changes and T cell activation , 1998, European journal of immunology.

[42]  H. Hamada,et al.  Functional analysis of CD82 in the early phase of T cell activation: roles in cell adhesion and signal transduction , 1998, European journal of immunology.

[43]  G. Michalopoulos,et al.  Expression of HGF and cMet in the developing and adult brain. , 1997, Brain research. Developmental brain research.

[44]  F. Berditchevski,et al.  Transmembrane-4 superfamily proteins CD81 (TAPA-1), CD82, CD63, and CD53 specifically associated with integrin alpha 4 beta 1 (CD49d/CD29). , 1996, Journal of immunology.

[45]  T. Nakamura,et al.  Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. , 1995, Brain research. Molecular brain research.

[46]  J. Barrett,et al.  KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. , 1995, Science.

[47]  Tetsuo Noda,et al.  Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor , 1995, Nature.

[48]  M. Sharpe,et al.  Scatter factor/hepatocyte growth factor is essential for liver development , 1995, Nature.

[49]  E. Castrén,et al.  Expression and functional interaction of hepatocyte growth factor- scatter factor and its receptor c-met in mammalian brain , 1994, The Journal of cell biology.

[50]  J. Salzer,et al.  The myelin-associated glycoproteins: membrane disposition, evidence of a novel disulfide linkage between immunoglobulin-like domains, and posttranslational palmitylation , 1990, The Journal of cell biology.

[51]  M. Waterfield,et al.  Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. , 1988, Nature.