The IRS-pathway operates distinctively from the stat-pathway in hematopoietic cells and transduces common and distinct signals during engagement of the insulin or interferon-α receptors

Shahab Uddin, Eleanor N. Fish, Dorie Sher, Concetta Gardziola, Oscar R. Colamonici, Merrill Kellum, Paula M. Pitha, Morris F. White, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Binding of interferon-α (IFN-α) to its receptor on hematopoletic cells activates the signal transducers and activators of transcription (Stat)- and insulin receptor substrate (IRS)pathways, and regulates expression of antiproliferative and antiviral activities. However, it remains unknown whether these two pathways cooperate in the generation of IFN-α responses or function independently, and whether IRS-proteins transduce distinct downstream signals in response to IFNs or insulin/insulin-like growth factor (IGF)-1-mediated activation. Our data show that in response to IFN-α treatment, IRS-1 functions selectively as a docking protein for the SH2 domains of the p85 subunit of the PI 3'-kinase, but not the SH2 domain of Grb-2 which is engaged during insulin/IGF-1 signaling. In studies with THP-1 human myelomo-nocytic cells and 32D mouse myeloid cells, which are IRS- defective, we found that the IFN-α-regulated activation of Stat-1, Stat-2, and Stat-3 does not require the function of the IRS-system. Furthermore, THP- 1 cells are responsive to the protective effect of IFN-α against vesicular stomatitis virus. Both 32D and THP-1 cells were resistant to the growth inhibitory effect of IFN-α, but this effect was not reversible by expression of IRS-1 or IRS-2 alone in 32D cells. Taken altogether these data show that: (1) The IRS-system transduces common and distinct signals in response to IFN- α or insulin/IGF-1 stimulation of hematopoietic cells. (2) The IRS-pathway operates separately from the Star-pathway, and its function is not essential for the generation of the antiviral effect of IFN-α. (3) Neither the IRS- nor the Star-pathways alone are sufficient to mediate the antiproliferative effects of IFN-α in hematopoietic cells, and additional signaling elements are required.

Original languageEnglish (US)
Pages (from-to)2574-2582
Number of pages9
JournalBlood
Volume90
Issue number7
StatePublished - Oct 1 1997

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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