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  The Cytokine-inducible Scr Homology Domain-containing Protein Negatively Regulates Signaling by Promoting Apoptosis in Erythroid Progenitor Cells

Ketteler, R., Moghraby, C. S., Hsiao, J. G., Sandra, O., Lodish, H. F., & Klingmuller, U. (2003). The Cytokine-inducible Scr Homology Domain-containing Protein Negatively Regulates Signaling by Promoting Apoptosis in Erythroid Progenitor Cells. Journal of Biological Chemistry, 278, 2654-2660.

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 Creators:
Ketteler, Robin1, Author           
Moghraby, Chetal S.1, Author           
Hsiao, Jonathan G.2, Author
Sandra, Olivier1, Author           
Lodish, Harvey F., Author
Klingmuller, Ursula2, Author
Affiliations:
1Spemann Laboratory, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243655              
2Max Planck Society, ou_persistent13              

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 Abstract: The small cytokine-inducible SH2 domain-containing protein (CIS) has been implicated in the negative regulation of signaling through cytokine receptors. CIS reduces growth of erythropoietin receptor (EpoR)-dependent cell lines, but its role in proliferation, differentiation, and survival of erythroid progenitor cells has not been resolved. To dissect the function of CIS in cell lines and erythroid progenitor cells, we generated green fluorescent protein (GFP)-tagged versions of wild type CIS, a mutant harboring an inactivated SH2 domain (CIS R107K), and a mutant with a deletion of the SOCS Box (CISΔBox). Retroviral expression of the GFP fusion proteins in BaF3-EpoR cells revealed that both Tyr-401 in the EpoR and an intact SH2 domain within CIS are prerequisites for receptor recruitment. As a consequence, both are essential for the growth inhibitory effect of CIS, whereas the CIS SOCS box is dispensable. Accordingly, the retroviral expression of GFP-CIS but not GFP-CIS R107K impaired proliferation of erythroid progenitor cells in colony assays. Erythroid differentiation was unaffected by either protein. Interestingly, apoptosis of erythroid progenitor cells was increased upon GFP-CIS expression and this required the presence both of an intact SH2 domain and the SOCS box. Thus, CIS negatively regulates signaling at two levels, apoptosis and proliferation, and thereby sets a threshold for signal transduction.

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Language(s): eng - English
 Dates: 2003
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: eDoc: 175555
ISI: 000180562000077
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Title: Journal of Biological Chemistry
  Alternative Title : J. Biol. Chem.
Source Genre: Journal
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Pages: - Volume / Issue: 278 Sequence Number: - Start / End Page: 2654 - 2660 Identifier: ISSN: 0021-9258