The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/8/561/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 4, August 18, 1997 561-568

Article

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, and Rafeul Alam

* From the University of Texas Medical Branch, Department of Internal Medicine, Allergy and Immunology Division, Galveston, TX 77555-0762

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 (βc) chain of the IL-5 receptor (IL-5βcR). The association of SHPTP2 with IL-5βcR was reconstituted using a synthetic phosphotyrosine-containing peptide, βc 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 βc receptor and Grb2 and its early activation are required for the coupling of the receptor to the Ras signaling pathway and for prevention of eosinophil death by IL-5.

Address correspondence to Dr. Rafeul Alam, The University of Texas Medical Branch, Department of Internal Medicine, Rt-0672, Galveston, TX 77555-0762. Phone: 409-772-3411; FAX: 409-772-5841; E-mail: ralam{at}impo1.utmb.edu

1 Abbreviations used in this paper: βc, β common; ITIM, immunoreceptor tyrosine-based inhibitory motif; MAP, microtubule-associated protein; ODN, oligodeoxynucleotide; PDGF, platelet-derived growth factor; PTP, protein tyrosine phosphatase; SH, Src homology.


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