Contribution of the Box 1 and Box 2 motifs of cytokine receptors to Jak1 association and activation

Anna Usacheva, Raudel Sandoval, Paul Domanski, Sergei V. Kotenko, Keats Nelms, Mark A. Goldsmith, Oscar R. Colamonici

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34 Scopus citations

Abstract

Kinases of the Jak family (Jak1/2/3 and Tyk2) interact with the membrane proximal domain of different cytokine receptors and play a critical role in the activation of cytokine and growth factor signaling pathways. In this report we demonstrate that both the Box 1 and Box 2 motif collaborate in the association and activation of Jak1 by type I interferons. Mutational analysis of the β chain of type I interferon receptor (IFNαRβL/IFNAR2) revealed that Box 1 plays a more significant role in activation than in the association with Jak1 On the contrary, the Box 2 motif contributes more to the association with Jak1 than to kinase activation. Additionally, the study of the Jak1 binding sites on the IL2 receptor β (IL2Rβ), IFNγRα/IFNGR1, and IL10Rα/IL10R1 chains suggests that cytokine receptors have two different kinds of interaction with Jakl. One form of interaction involves the Box 1 and the previously described Box 2 motif, which we now designate as Box 2A, characterized by the VEVI and LEVL sequences present in IFNαRβL/IFNAR2 and IL2Rβ subunits, respectively. The second form of interaction requires a motif termed Box 2B, which is present in the IFNγRα/IFNGR1 (SILLPKS) and IL10Rα/IL10R1 (SVLLFKK) chains. Interestingly, Box 2B localizes close to the membrane region (8-10 amino acids from the membrane) similar to Box 1, whereas Box 2A is more distal (38-58 amino acids from the membrane).

Original languageEnglish (US)
Pages (from-to)48220-48226
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number50
DOIs
StatePublished - Dec 13 2002

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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