Tyrosine residues of the granulocyte colony-stimulating factor receptor transmit proliferation and differentiation signals in murine bone marrow cells

Akbarzadeh, S; Ward, AC; McPhee, DOM; Alexander, WS; Lieschke, GJ; Layton, JE

Author(s): Akbarzadeh, S; Ward, AC; McPhee, DOM; Alexander, WS; Lieschke, GJ; Layton, JE;
Details: Publication Year 2002-02-01,Volume 99,Issue #3,Page 879-887
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: Granulocyte colony-stimulating factor (G-CSF) is the major regulator of granulopoiesis and acts through binding to its specific receptor (G-CSF-R) on neutrophilic granulocytes. Previous studies of signaling from the 4 G-CSF-R cytoplasmic tyrosine residues used model cell lines that may have idiosyncratic, nonphysiological responses. This study aimed to identify specific signals transmitted by the receptor tyrosine residues in primary myeloid cells. To bypass the presence of endogenous G-CSF-R, a chimeric receptor containing the extracellular domain of the epidermal growth factor receptor in place of the entire extracellular domain of the G-CSF-R was used. A series of chimeric receptors containing tyrosine mutations to phenylalanine, either individually or collectively, was constructed and expressed in primary bone marrow cells from G-CSF-deficient mice. Proliferation and differentiation responses of receptor-expressing bone marrow cells stimulated by epidermal growth factor were measured. An increased 50% effective concentration to stimulus of the receptor Y-null mutant indicated that specific signals from tyrosine residues were required for cell proliferation, particularly at low concentrations of stimulus. Impaired responses by mutant receptors implicated G-CSF-R Y-764 in cell proliferation and Y-729 in granulocyte differentiation signaling. In addition, different sensitivities to ligand stimulation between mutant receptors indicated that G-CSF-R Y-744 and possibly Y-729 have an inhibitory role in cell proliferation. STAT activation was not affected by tyrosine mutations, whereas ERK activation appeared to depend, at least in part, on Y-764. These observations have suggested novel roles for the G-CSF-R tyrosine residues in primary cells that were not observed previously in studies in cell lines. (C) 2002 by The American Society of Hematology.
Publisher: AMER SOC HEMATOLOGY
Keywords: G-CSF RECEPTOR; CYTOPLASMIC DOMAIN; ERYTHROPOIETIN RECEPTOR; DEPENDENT ACTIVATION; RAPID ACTIVATION; DISTINCT REGIONS; PROTEIN; GENE; BINDING; STAT3
Publisher's Version: https://doi.org/10.1182/blood.V99.3.879
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-02-01 12:00:00