The extracellular and transmembrane domains of the γC and interleukin (IL)-13 receptor α1 chains, not their cytoplasmic domains, dictate the nature of signaling responses to IL-4 and IL-13

Nicola M. Heller, Xiulan Qi, Franck Gesbert, Achsah D. Keegan

Research output: Contribution to journalArticlepeer-review

Abstract

Previously, we demonstrated that the -Csubunit of type I IL-4 receptor was required for robust tyrosine phosphorylation of the downstream adapter protein, IRS-2, correlating with the expression of genes (ArgI, Retnla, and Chi3l3) characteristic of alternatively activated macrophages. We located an I4R-like motif (IRS-2 docking sequence) in the -C cytoplasmic domain but not in the IL-13R-1. Thus, we predicted that the -C tail directed enhanced IRS-2 phosphorylation. To test this, IL-4 signaling responses were examined in a mutant of the key I4R motif tyrosine residue (Y325F) and different -C truncation mutants (-285, -308, -318, -323, and -FULL LENGTH (FL)) co-expressed in L-cells or CHO cells with wild-type (WT) IL-4R-. Surprisingly, IRS-1 phosphorylation was not diminished in Y325F L-cell mutants suggesting Tyr-325 was not required for the robust insulin receptor substrate response. IRS-2, STAT6, and JAK3 phosphorylation was observed in CHO cells expressing -323 and -FL but not in -318 and -285 mutants. In addition, when CHO cells expressed -318, -323, or -FL with IL-2R-, IL-2 induced phospho-STAT5 only in the -323 and -FL clones. Our data suggest that a smaller (5 amino acid) interval than previously determined is necessary for JAK3 activation/ -C-mediated signaling in response to IL-4 and IL-2. Chimeric receptor chains of the -C tail fused to the IL-13R-1 extracellular and transmembrane domain did not elicit robust IRS-2 phosphorylation in response to IL-13 suggesting that the extracellular/ transmembrane domains of the IL-4/IL-13 receptor, not the cytoplasmic domains, control signaling efficiency. Understanding this pathway fully will lead to rational drug design for allergic disease.

Original languageEnglish (US)
Pages (from-to)31948-31961
Number of pages14
JournalJournal of Biological Chemistry
Volume287
Issue number38
DOIs
StatePublished - Sep 14 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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