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

Wenbo Xu, Michael Shy, John Kamholz, Lisa Elferink, Gang Xu, Jack Lilien, Janne Balsamo

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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, PKCalpha 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 PKCalpha 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.

Original languageEnglish (US)
Pages (from-to)439-446
Number of pages8
JournalThe Journal of cell biology
Volume155
Issue number3
StatePublished - Oct 29 2001

Fingerprint

Point Mutation
Phosphorylation
Myelin Proteins
Charcot-Marie-Tooth Disease
Mutation
Peripheral Nervous System
Peripheral Nervous System Diseases
Serine
Immunoglobulins
Carrier Proteins
Amino Acids

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination. / Xu, Wenbo; Shy, Michael; Kamholz, John; Elferink, Lisa; Xu, Gang; Lilien, Jack; Balsamo, Janne.

In: The Journal of cell biology, Vol. 155, No. 3, 29.10.2001, p. 439-446.

Research output: Contribution to journalArticle

Xu, Wenbo ; Shy, Michael ; Kamholz, John ; Elferink, Lisa ; Xu, Gang ; Lilien, Jack ; Balsamo, Janne. / Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination. In: The Journal of cell biology. 2001 ; Vol. 155, No. 3. pp. 439-446.
@article{e4f9e65082564594a2b606bfd856fd5c,
title = "Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination",
abstract = "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, PKCalpha 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 PKCalpha 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.",
author = "Wenbo Xu and Michael Shy and John Kamholz and Lisa Elferink and Gang Xu and Jack Lilien and Janne Balsamo",
year = "2001",
month = "10",
day = "29",
language = "English (US)",
volume = "155",
pages = "439--446",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "3",

}

TY - JOUR

T1 - Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination

AU - Xu, Wenbo

AU - Shy, Michael

AU - Kamholz, John

AU - Elferink, Lisa

AU - Xu, Gang

AU - Lilien, Jack

AU - Balsamo, Janne

PY - 2001/10/29

Y1 - 2001/10/29

N2 - 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, PKCalpha 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 PKCalpha 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.

AB - 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, PKCalpha 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 PKCalpha 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.

UR - http://www.scopus.com/inward/record.url?scp=84924094149&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924094149&partnerID=8YFLogxK

M3 - Article

VL - 155

SP - 439

EP - 446

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 3

ER -