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Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells

Hermans, Mirjam H. A., van de Geijn, Gert-Jan, Antonissen, Claudia, Gits, Judith, van Leeuwen, Daphne, Ward, Alister and Touw, Ivo P. 2003, Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells, Blood, vol. 101, no. 7, pp. 2584-2590.

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Title Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells
Author(s) Hermans, Mirjam H. A.
van de Geijn, Gert-Jan
Antonissen, Claudia
Gits, Judith
van Leeuwen, Daphne
Ward, Alister
Touw, Ivo P.
Journal name Blood
Volume number 101
Issue number 7
Start page 2584
End page 2590
Publisher American Society of Hematology
Place of publication Washington, D.C.
Publication date 2003-04-01
ISSN 0006-4971
1528-0020
Summary Granulocyte colony-stimulating factor (G-CSF) is the major regulator of neutrophil production. Studies in cell lines have established that conserved tyrosines Y704, Y729, Y744, Y764 within the cytoplasmic domain of G-CSF receptor (G-CSF-R) contribute significantly to G-CSF-induced proliferation, differentiation and cell survival. However, it is unclear whether these tyrosines are equally important under more physiological conditions. Here, we investigated how individual G-CSF-R tyrosines affect G-CSF responses of primary myeloid progenitors. We generated GCSF- R deficient mice and transduced their bone marrow cells with tyrosine "null" mutant (mO), single tyrosine "add back" mutants or wild type (WT) receptors. G-CSFinduced responses were determined in primary colony assays, serial replatings and suspension cultures. We show that removal of all tyrosines had no major influence on primary colony growth. However, adding back Y764 strongly enhanced proliferativeresponses, which was reverted by inhibition of ERK activitity. Y729, which we found to be associated with the suppressor of cytokine signaling, SOCS3, had a negative effect on colony formation. After repetitive replatings, the clonogenic capacities of cells expressing mO gradually dropped compared to WT. The presence of Y729, but also Y704 and Y744, both involved in activation of STAT3, further reduced replating
efficiencies. Conversely, Y764 greatly elevated the clonogenic abilities of myeloid progenitors, resulting in a >104–fold increase of colony forming cells over mO after the fifth replating. These findings suggest that tyrosines in the cytoplasmic domain of G-CSF-R, although dispensable for G-CSF-induced colony growth, recruit signaling mechanisms that regulate the maintenance and outgrowth of myeloid progenitor cells.
Language eng
Field of Research 060110 Receptors and Membrane Biology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2003, The American Society of Hematology.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30008630

Document type: Journal Article
Collection: School of Biological and Chemical Sciences
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Created: Mon, 13 Oct 2008, 15:37:31 EST