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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- Receptors
Shahab Uddin,
Eleanor N. Fish,
Dorie Sher,
Concetta Gardziola,
Oscar R. Colamonici,
Merrill Kellum,
Paula M. Pitha,
Morris F. White, and
Leonidas C. Platanias
From the Section of Hematology-Oncology, Department of Medicine, University of Illinois at Chicago and West Side Veterans Affairs Hospital, IL; the Department of Medical Genetics and Microbiology, University of Toronto, Ontario, Canada; the Division of Hematology-Oncology, Loyola University of Chicago and Hines VA Hospital, Maywood, IL; the Department of Pathology, University of Tennessee, Memphis; Oncology Center, Johns Hopkins University, Baltimore, MD; and Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.
Binding of interferon- (IFN-) to its receptor on hematopoietic 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- 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- 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 myelomonocytic cells and 32D mouse myeloid cells, which are IRS-defective, we found that the IFN--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- against vesicular stomatitis virus. Both 32D and THP-1 cells were resistant to the growth inhibitory effect of IFN-, 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- or insulin/IGF-1 stimulation of hematopoietic cells. (2) The IRS-pathway operates separately from the Stat-pathway, and its function is not essential for the generation of the antiviral effect of IFN-. (3) Neither the IRS- nor the Stat-pathways alone are sufficient to mediate the antiproliferative effects of IFN- in hematopoietic cells, and additional signaling elements are required.
Blood, Vol. 90 No. 7 (October 1), 1997:
pp. 2574-2582
© 1997 by The American Society of Hematology.
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