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Published online 22 October 2001. doi:10.1083/jcb.200107114
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© The Rockefeller University Press, 0021-9525/2001/10/439 $5.00
The Journal of Cell Biology, Volume 155, Number 3, October 29, 2001 439-446

Article

Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination



Wenbo Xu1, Michael Shy1, John Kamholz1, Lisa Elferink2, Gang Xu3, Jack Lilien3 and Janne Balsamo3

1 Department of Neurology and the Center for Molecular Medicine and Genetics, Wayne State University Detroit, MI 48202
2 Biomedical Marine Institute and Department of Biophysics and Physiology, Galveston, TX 77555
3 Department of Biological Sciences, The University of Iowa, Iowa City, IA 52242

Address correspondence to Jack Lilien, Dept. of Biological Sciences, The University of Iowa, 138 Biology Bldg., Iowa City, IA 52242-1324. Tel.: (319) 353-2969. Fax: (319) 335-0081. E-mail: jack-lilien{at}uiowa.edu

Mutations in P0 (MPZ), the major myelin protein of the peripheral nervous system, cause the inherited demyelinating neuropathy Charcot-Marie-Tooth disease type 1B. P0 is a member of the immunoglobulin superfamily and functions as a homophilic adhesion molecule. We now show that point mutations in the cytoplasmic domain that modify a PKC target motif (RSTK) or an adjacent serine residue abolish P0 adhesion function and can cause peripheral neuropathy in humans. Consistent with these data, PKC{alpha} along with the PKC binding protein RACK1 are immunoprecipitated with wild-type P0, and inhibition of PKC activity abolishes P0-mediated adhesion. Point mutations in the RSTK target site that abolish adhesion do not alter the association of PKC with P0; however, deletion of a 14 amino acid region, which includes the RSTK motif, does abolish the association. Thus, the interaction of PKC{alpha} with the cytoplasmic domain of P0 is independent of specific target residues but is dependent on a nearby sequence. We conclude that PKC-mediated phosphorylation of specific residues within the cytoplasmic domain of P0 is necessary for P0-mediated adhesion, and alteration of this process can cause demyelinating neuropathy in humans.

Key Words: P0; adhesion; myelination; PKC; RACK1


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