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-alpha receptors.
Binding of interferon-alpha (IFN-alpha) 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-alpha 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-alpha 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-alpha-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-alpha against vesicular stomatitis virus. Both 32D and THP-1 cells were resistant to the growth inhibitory effect of IFN-alpha, 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-alpha or insulin/lGF-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-alpha. (3) Neither the IRS- nor the Stat-pathways alone are sufficient to mediate the antiproliferative effects of IFN-alpha in hematopoietic cells, and additional signaling elements are required.
Uddin
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S
Department of Medicine, University of Illinois at Chicago and West Side Veterans Affairs Hospital, 60607-7173, USA.
Fish
E N
EN
Sher
D
D
Gardziola
C
C
Colamonici
O R
OR
Kellum
M
M
Pitha
P M
PM
White
M F
MF
Platanias
L C
LC
D000818:Animals; D002051:Burkitt Lymphoma / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology*; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000187:drug effects / Q000502:physiology*; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D004268:DNA-Binding Proteins; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin