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Both the Suppressor of Cytokine Signaling 1 (SOCS-1) Kinase Inhibitory Region and SOCS-1 Mimetic Bind to JAK2 Autophosphorylation Site: Implications for the Development of a SOCS-1 Antagonist¹

Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611

Suppressor of cytokine signaling (SOCS)-1 protein modulates signaling by IFN- by binding to the autophosphorylation site of JAK2 and by targeting bound JAK2 to the proteosome for degradation. We have developed a small tyrosine kinase inhibitor peptide (Tkip) that is a SOCS-1 mimetic. Tkip is compared in this study with the kinase inhibitory region (KIR) of SOCS-1 for JAK2 recognition, inhibition of kinase activity, and regulation of IFN--induced biological activity. Tkip and a peptide corresponding to the KIR of SOCS-1, ⁽⁵³⁾DTHFRTFRSHSDYRRI⁽⁶⁸⁾ (SOCS1-KIR), both bound similarly to the autophosphorylation site of JAK2, JAK2(1001–1013). The peptides also bound to JAK2 peptide phosphorylated at Tyr¹⁰⁰⁷, pJAK2(1001–1013). Dose-response competitions suggest that Tkip and SOCS1-KIR similarly recognize the autophosphorylation site of JAK2, but probably not precisely the same way. Although Tkip inhibited JAK2 autophosphorylation as well as IFN--induced STAT1- phosphorylation, SOCS1-KIR, like SOCS-1, did not inhibit JAK2 autophosphorylation but inhibited STAT1- activation. Both Tkip and SOCS1-KIR inhibited IFN- activation of Raw 264.7 murine macrophages and inhibited Ag-specific splenocyte proliferation. The fact that SOCS1-KIR binds to pJAK2(1001–1013) suggests that the JAK2 peptide could function as an antagonist of SOCS-1. Thus, pJAK2(1001–1013) enhanced suboptimal IFN- activity, blocked SOCS-1-induced inhibition of STAT3 phosphorylation in IL-6-treated cells, enhanced IFN- activation site promoter activity, and enhanced Ag-specific proliferation. Furthermore, SOCS-1 competed with SOCS1-KIR for pJAK2(1001–1013). Thus, the KIR region of SOCS-1 binds directly to the autophosphorylation site of JAK2 and a peptide corresponding to this site can function as an antagonist of SOCS-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants NS051245 and AI 056152 (to H.M.J.).

² Current address: Department of Physical Sciences and Mathematics, Florida Gulf Coast University, Fort Myers, FL 33965.

³ Current address: Department of Biology, Fayetteville State University, Fayetteville, NC 28301.

⁴ Address correspondence and reprint requests to Dr. Howard M. Johnson, Department of Microbiology and Cell Science, University of Florida, P.O. Box 110700, Building 981, Room 1052, Gainesville, FL 32611. E-mail address: johnsonh{at}ufl.edu

⁵ Abbreviations used in this paper: IFNGR, IFN- receptor; SOCS, suppressor of cytokine signaling; EGFR, epidermal growth factor receptor; Tkip, tyrosine kinase inhibitor peptide; SH2, Src homology 2; KIR, kinase inhibitory region; lipo, lipophilic; MuIFN, murine IFN-; GAS, IFN--activated sequence; MBP, myelin basic protein; EMCV, encephalomyocarditis virus; p, phosphorylated; ESS, extended SH2 sequence; siRNA, small-interfering RNA; EAE, experimental allergic encephalomyelitis.

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