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J Biol Chem, Vol. 273, Issue 31, 19411-19418, July 31, 1998

Cytoplasmic Domains of the Human Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Receptor  Chain (hc) Responsible for Human GM-CSF-induced Myeloid Cell Differentiation

Tetsuya Matsuguchi, Michael B. Lilly^¶, and Andrew S. Kraft

From the  Division of Medical Oncology, University of Colorado Health Science Center, Denver, Colorado 80262 and the ^¶ Division of Medical Oncology, University of Washington and Veterans Affairs Medical Center, Seattle, Washington 98108

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates differentiation, survival, and proliferation of myeloid progenitor cells. The biologic actions of GM-CSF are mediated by its binding to the  and  subunits of the GM-CSF receptor (GM-CSFR and c, respectively). To determine whether identical regions of the c protein mediate both cell growth and differentiation, we expressed cDNA constructs encoding the human wild-type (897 amino acids) and truncated c (hc) subunits along with the wild-type human GM-CSFR subunit in the murine WT19 cell line, an FDC-P1-derived cell line that differentiates toward the monocytic lineage in response to murine GM-CSF. Whereas the WT19 cell line carrying the C-terminal deleted hc subunit of 627 amino acids was still able to grow in human GM-CSF (hGM-CSF), 681 amino acids of the hc were necessary for cell differentiation. The addition of hGM-CSF to WT19 cell lines containing the hc627 subunit stimulated the phosphorylation of ERK (extracellular signal-regulated kinase) and induced the tyrosine-phosphorylation of SHP-2 and STAT5, suggesting that the activation of these molecules is insufficient to mediate the induction of differentiation. A point mutation of tyrosine 628 to phenylalanine (Y628F) within hc681 abolished the ability of hGM-CSF to induce differentiation. Our results indicate that the signals required for hGM-CSF-induced differentiation and cell growth are mediated by different regions of the hc subunit.

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