Tyrosine phosphorylation of myelin P(0) and its implication in signal transduction.
P(0), a major structural protein of peripheral myelin, belongs to the immunoglobulin superfamily. Sequence comparison of P(0) with PZR, a tyrosine phosphatase SHP-2 binding protein we recently cloned, revealed the presence of an immunoreceptor tyrosine-based inhibitory motif (ITIM) in the intracellular portion of the P(0) molecule. To study the role of this putative ITIM in signal transduction, we have expressed P(0) in HT-1080 and 293 cells. Stimulation of the transfected cells with pervanadate, a powerful inhibitor of tyrosine phosphatases, resulted in tyrosine phosphorylation of P(0) and its association with several tyrosine-phosphorylated proteins. Mutation of Y(220) embedded in the ITIM to phenylalanine abolished the tyrosine phosphorylation and the association. Tyrosine phosphorylation of P(0) and its association with other signaling proteins were also observed in pervanadate-treated RN22 Schwannoma cells, which express endogenous P(0). Furthermore, injection of pervanadate induced tyrosine phosphorylation of P(0) in peripheral nerves of newborn but not adult mice. The physiological importance of the ITIM in P(0) is implied by the fact that a naturally occurred P(0) mutant with a disrupted ITIM has a dominant role in causing Dejerine-Scotts syndrome. Taken together, P(0) is phosphorylated on Try(220). The presence of an ITIM in P(0) and its ability to mediate protein-protein interaction through tyrosine phosphorylation indicate that P(0) is not merely a structural protein but may also be a crucial player in cell signaling.
Xu
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Hematology/Oncology Division, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, 37232-6305, USA.
Zhao
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Sui
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Xu
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Zhao
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D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D016384:Consensus Sequence; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D018993:Myelin P0 Protein / Q000737:chemistry / Q000378:metabolism*; D009442:Neurilemmoma; D010649:Phenylalanine; D010766:Phosphorylation; D019000:Phosphotyrosine; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine; D014638:Vanadates / Q000494:pharmacology
D018993:Myelin P0 Protein; D011994:Recombinant Proteins; C076715:pervanadate; D019000:Phosphotyrosine; D014638:Vanadates; D014443:Tyrosine; D010649:Phenylalanine