Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival

Konrad Pazdrak, Tetsuya Adachi, Rafeul Alam

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    Abstract

    Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5-stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with β common (β(c)) chain of the IL-5 receptor (IL-5β(c)R). The association of SHPTP2 with IL-5β(c)R was reconstituted using a synthetic phosphotyrosine-containing peptide, β(c) 605-624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612→F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated β(c) receptor and Grb2 and its early activation are required for the coupling of the receptor to the gas signaling pathway and for prevention of eosinophil death by IL-5.

    Original languageEnglish (US)
    Pages (from-to)561-568
    Number of pages8
    JournalJournal of Experimental Medicine
    Volume186
    Issue number4
    DOIs
    StatePublished - Aug 18 1997

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    Interleukin-5 Receptors
    Protein Phosphatase 2
    Protein Tyrosine Phosphatases
    Phosphoric Monoester Hydrolases
    Eosinophils
    Interleukin-5
    Signal Transduction
    Tyrosine
    Phosphotyrosine
    Phosphorylation
    Peptides
    2-tyrosine
    Microtubule-Associated Proteins
    Antisense Oligonucleotides
    Protein-Tyrosine Kinases
    Protein Kinases

    ASJC Scopus subject areas

    • Immunology

    Cite this

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    title = "Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival",
    abstract = "Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5-stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with β common (β(c)) chain of the IL-5 receptor (IL-5β(c)R). The association of SHPTP2 with IL-5β(c)R was reconstituted using a synthetic phosphotyrosine-containing peptide, β(c) 605-624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612→F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated β(c) receptor and Grb2 and its early activation are required for the coupling of the receptor to the gas signaling pathway and for prevention of eosinophil death by IL-5.",
    author = "Konrad Pazdrak and Tetsuya Adachi and Rafeul Alam",
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    T1 - Src homology 2 protein tyrosine phosphatase (SHPTP2)/Src homology 2 phosphatase 2 (SHP2) tyrosine phosphatase is a positive regulator of the interleukin 5 receptor signal transduction pathways leading to the prolongation of eosinophil survival

    AU - Pazdrak, Konrad

    AU - Adachi, Tetsuya

    AU - Alam, Rafeul

    PY - 1997/8/18

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    N2 - Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5-stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with β common (β(c)) chain of the IL-5 receptor (IL-5β(c)R). The association of SHPTP2 with IL-5β(c)R was reconstituted using a synthetic phosphotyrosine-containing peptide, β(c) 605-624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612→F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated β(c) receptor and Grb2 and its early activation are required for the coupling of the receptor to the gas signaling pathway and for prevention of eosinophil death by IL-5.

    AB - Interleukin-5 (IL-5) regulates the growth and function of eosinophils. It induces rapid tyrosine phosphorylation of Lyn and Jak2 tyrosine kinases. The role of tyrosine phosphatases in IL-5 signal transduction has not been investigated. In this study, we provide first evidence that SH2 protein tyrosine phosphatase 2 (SHPTP2) phosphotyrosine phosphatase plays a key role in prevention of eosinophil death by IL-5. We found that IL-5 produced a rapid activation and tyrosine phosphorylation of SHPTP2 within 1 min. The tyrosine phosphorylated SHPTP2 was complexed with the adapter protein Grb2 in IL-5-stimulated eosinophils. Furthermore, SHPTP2 appeared to physically associate with β common (β(c)) chain of the IL-5 receptor (IL-5β(c)R). The association of SHPTP2 with IL-5β(c)R was reconstituted using a synthetic phosphotyrosine-containing peptide, β(c) 605-624, encompassing tyrosine (Y)612. The binding to the phosphotyrosine-containing peptide increased the phosphatase activity of SHPTP2, whereas the same peptide with the phosphorylated Y612→F mutation did not activate SHPTP2. Only SHPTP2 antisense oligonucleotides, but not sense SHPTP2, could inhibit tyrosine phosphorylation of microtubule-associated protein kinase, and reverse the eosinophil survival advantage provided by IL-5. Therefore, we conclude that the physical association of SHPTP2 with the phosphorylated β(c) receptor and Grb2 and its early activation are required for the coupling of the receptor to the gas signaling pathway and for prevention of eosinophil death by IL-5.

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