Myelin protein zero/P0 phosphorylation and function require an adaptor protein linking it to RACK1 and PKCα

Point mutations in the cytoplasmic domain of myelin protein zero (P0; the major myelin protein in the peripheral nervous system) that alter a protein kinase Cα (PKCα) substrate motif (198HRSTK201) or alter serines 199 and/or 204 eliminate P0-mediated adhesion. Mutation in the PKCα substrate motif (R198S) also causes a form of inherited peripheral neuropathy (Charcot Marie Tooth disease [CMT] 1B), indicating that PKCα-mediated phosphorylation of P0 is important for myelination. We have now identified a 65-kD adaptor protein that links P0 with the receptor for activated C kinase 1 (RACK1). The interaction of p65 with P0 maps to residues 179–197 within the cytoplasmic tail of P0. Mutations or deletions that abolish p65 binding reduce P0 phosphorylation and adhesion, which can be rescued by the substitution of serines 199 and 204 with glutamic acid. A mutation in the p65-binding sequence G184R occurs in two families with CMT, and mutation of this residue results in the loss of both p65 binding and adhesion function.

[1]  J. Lilien,et al.  The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of beta-catenin. , 2005, Current opinion in cell biology.

[2]  D. Cheresh,et al.  Tyrosine Phosphorylation of VE-cadherin Prevents Binding of p120- and β-Catenin and Maintains the Cellular Mesenchymal State* , 2005, Journal of Biological Chemistry.

[3]  Peter J. Brophy,et al.  Mechanisms of axon ensheathment and myelin growth , 2005, Nature Reviews Neuroscience.

[4]  C. Wessig,et al.  Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder , 2004, The Journal of cell biology.

[5]  Richard A Lewis,et al.  Phenotypic clustering in MPZ mutations. , 2004, Brain : a journal of neurology.

[6]  Donna J. Webb,et al.  FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly , 2004, Nature Cell Biology.

[7]  J. Eichberg.  Myelin P0: New Knowledge and New Roles , 2002, Neurochemical Research.

[8]  Jean-Antoine Girault,et al.  Development of nodes of Ranvier , 2002, Current Opinion in Neurobiology.

[9]  U. Suter,et al.  Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. , 2002, Human molecular genetics.

[10]  J. Lilien,et al.  Turn‐off, drop‐out: Functional state switching of cadherins , 2002, Developmental dynamics : an official publication of the American Association of Anatomists.

[11]  S. Scherer,et al.  Recent progress on the molecular organization of myelinated axons , 2002, Journal of the peripheral nervous system : JPNS.

[12]  S. Scherer,et al.  Protein Zero Is Necessary for E-Cadherin-Mediated Adherens Junction Formation in Schwann Cells , 2001, Molecular and Cellular Neuroscience.

[13]  M. Shy,et al.  Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination , 2001, The Journal of cell biology.

[14]  P K Thomas,et al.  Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin. , 2001, Brain : a journal of neurology.

[15]  M. Shy,et al.  Absence of P0 leads to the dysregulation of myelin gene expression and myelin morphogenesis , 2000, Journal of neuroscience research.

[16]  Aldo Quattrone,et al.  Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2 , 2000, Nature Genetics.

[17]  Z. Zhao,et al.  Tyrosine phosphorylation of myelin P(0) and its implication in signal transduction. , 2000, Biochemical and biophysical research communications.

[18]  M. Shy,et al.  The Absence of Myelin P0 Protein Produces a Novel Molecular Phenotype in Schwann Cell , 1999, Annals of the New York Academy of Sciences.

[19]  C. van Broeckhoven,et al.  An adhesion test system based on Schneider cells to determine genotype-phenotype correlations for mutated P0 proteins. , 1998, Genetic analysis : biomolecular engineering.

[20]  S. Scherer,et al.  Heterozygous P0 knockout mice develop a peripheral neuropathy that resembles chronic inflammatory demyelinating polyneuropathy (CIDP). , 1997, Journal of neuropathology and experimental neurology.

[21]  M. Filbin,et al.  Dominant-negative effect on adhesion by myelin Po protein truncated in its cytoplasmic domain , 1996, The Journal of cell biology.

[22]  W. Hendrickson,et al.  Crystal Structure of the Extracellular Domain from P0, the Major Structural Protein of Peripheral Nerve Myelin , 1996, Neuron.

[23]  J. Lupski,et al.  Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination , 1996, Neuron.

[24]  E. Chan,et al.  cDNA cloning and characterization of a novel nucleolar protein. , 1996, Molecular biology of the cell.

[25]  J. Eichberg,et al.  Phosphorylation of myelin proteins: Recent advances , 1996, Neurochemical Research.

[26]  M. Schachner,et al.  Protein zero (P0)–deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies , 1995, Nature Genetics.

[27]  D. D'urso,et al.  Protein zero, a nervous system adhesion molecule, triggers epithelial reversion in host carcinoma cells , 1995, The Journal of cell biology.

[28]  R. Brent,et al.  Interaction mating reveals binary and ternary connections between Drosophila cell cycle regulators. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Filbin,et al.  The cytoplasmic domain of the myelin P0 protein influences the adhesive interactions of its extracellular domain , 1994, The Journal of cell biology.

[30]  M. Filbin,et al.  Homophilic adhesion of the myelin P0 protein requires glycosylation of both molecules in the homophilic pair , 1993, The Journal of cell biology.

[31]  M. Schachner,et al.  Mouse P 0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons , 1992, Cell.

[32]  R. Pearlman,et al.  Isolation and characterization of a cDNA encoding a synaptonemal complex protein. , 1992, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[33]  M. Schachner,et al.  Recombinant peripheral myelin protein Po confers both adhesion and neurite outgrowth‐promoting properties , 1990, Journal of neuroscience research.

[34]  B. Trapp,et al.  Role of myelin Po protein as a homophilic adhesion molecule , 1990, Nature.

[35]  R. Axel,et al.  Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin , 1985, Cell.

[36]  A. Riggs,et al.  Genomic Sequencing , 2010 .

[37]  M. Shy,et al.  A molecular basis for hereditary motor and sensory neuropathy disorders , 2001, Current neurology and neuroscience reports.

[38]  J. Thorner,et al.  Interaction mating methods in two-hybrid systems , 2001 .

[39]  M. Shy,et al.  The absence of myelin P0 protein produces a novel molecular phenotype in Schwann cells. , 1999, Annals of the New York Academy of Sciences.

[40]  D. Pareyson,et al.  Heterozygous null mutation in the P0 gene associated with mild Charcot-Marie-Tooth disease. , 1999, Annals of the New York Academy of Sciences.

[41]  C. van Broeckhoven,et al.  Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies , 1999, Human mutation.

[42]  J. Eichberg,et al.  Phosphorylation of myelin protein: recent advances. , 1996, Neurochemical research.