The Soluble Granulocyte-Macrophage Colony-Stimulating Factor Receptor's Carboxyl-Terminal Domain Mediates Retention of the Soluble Receptor on the Cell Surface through Interaction with the Granulocyte-Macrophage Colony-Stimulating Factor Receptor β-Subunit†

Biochemistry ◽  
1998 ◽  
Vol 37 (40) ◽  
pp. 14113-14120 ◽  
Author(s):  
Elizabeth W. Murray ◽  
Carin Pihl ◽  
Stephen M. Robbins ◽  
Jay Prevost ◽  
Arati Mokashi ◽  
...  
Keyword(s):  
Cell Surface ◽  
Soluble Receptor ◽  
Β Subunit ◽  
Colony Stimulating Factor ◽  
Terminal Domain ◽  
Carboxyl Terminal Domain ◽  
Macrophage Colony Stimulating Factor ◽  
Carboxyl Terminal ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Coupling of Osteopontin and Its Cell Surface Receptor CD44 to the Cell Survival Response Elicited by Interleukin-3 or Granulocyte-Macrophage Colony-Stimulating Factor

2000 ◽  
Vol 20 (8) ◽  
pp. 2734-2742 ◽  
Author(s):  
Yi-Hung Lin ◽  
Chang-Jen Huang ◽  
Jyh-Rong Chao ◽  
Shui-Tsung Chen ◽  
Shern-Fwu Lee ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Surface Receptor ◽  
Β Subunit ◽  
Colony Stimulating Factor ◽  
Adhesion Protein ◽  
Gm Csf ◽  
Surface Receptor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT The receptors for interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) share a common β subunit, the distal cytoplasmic domain of which is essential for the promotion of cell survival by these two cytokines. Genes whose expression is specifically induced by signaling through the distal cytoplasmic domain of this receptor β subunit were screened by a subtraction cloning approach in derivatives of a mouse pro-B-cell line. One gene thus identified was shown to encode a protein highly homologous (with only 7 amino acid substitutions) to murine osteopontin (OPN), a secreted adhesion protein. Conditioned medium from cells expressing wild-type OPN, but not that from cells expressing a deletion mutant lacking residues 79 to 140, increased the viability of a non-OPN-producing cell line in the presence of human GM-CSF. Antibody blocking experiments revealed that OPN produced as a result of IL-3 or GM-CSF signaling was secreted into the medium and, through binding to its cell surface receptor, CD44, contributed to the survival-promoting activities of these two cytokines. Furthermore, coupling of the OPN-CD44 pathway to the survival response to IL-3 was also demonstrated in primary IL-3-dependent mouse bone marrow cells. These results thus show that induction of an extracellular adhesion protein and consequent activation of its cell surface receptor are important for the antiapoptotic activities of IL-3 and GM-CSF.

Saturation Mutagenesis of the β Subunit of the Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor Shows Clustering of Constitutive Mutations, Activation of ERK MAP Kinase and STAT Pathways, and Differential β Subunit Tyrosine Phosphorylation

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 1989-2002 ◽  
Author(s):  
Brendan J. Jenkins ◽  
Timothy J. Blake ◽  
Thomas J. Gonda
Keyword(s):  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Transmembrane Domain ◽  
Point Mutations ◽  
Saturation Mutagenesis ◽  
Β Subunit ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The high-affinity receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are heterodimeric complexes consisting of cytokine-specific  subunits and a common signal-transducing β subunit (hβc). We have previously demonstrated the oncogenic potential of this group of receptors by identifying constitutively activating point mutations in the extracellular and transmembrane domains of hβc. We report here a comprehensive screen of the entire hβc molecule that has led to the identification of additional constitutive point mutations by virtue of their ability to confer factor independence on murine FDC-P1 cells. These mutations were clustered exclusively in a central region of hβc that encompasses the extracellular membrane-proximal domain, transmembrane domain, and membrane-proximal region of the cytoplasmic domain. Interestingly, most hβc mutants exhibited cell type-specific constitutive activity, with only two transmembrane domain mutants able to confer factor independence on both murine FDC-P1 and BAF-B03 cells. Examination of the biochemical properties of these mutants in FDC-P1 cells indicated that MAP kinase (ERK1/2), STAT, and JAK2 signaling molecules were constitutively activated. In contrast, only some of the mutant β subunits were constitutively tyrosine phosphorylated. Taken together, these results highlight key regions involved in hβc activation, dissociate hβc tyrosine phosphorylation from MAP kinase and STAT activation, and suggest the involvement of distinct mechanisms by which proliferative signals can be generated by hβc. © 1998 by The American Society of Hematology.

scholarly journals Direct stimulation of cells expressing receptors for macrophage colony- stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1308-1314 ◽  
Author(s):  
J Stein ◽  
GV Borzillo ◽  
CW Rettenmier
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Cell Surface ◽  
Mononuclear Phagocytes ◽  
Biologically Active ◽  
Colony Stimulating Factor ◽  
Membrane Bound ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Secreted forms of macrophage colony-stimulating factor (M-CSF or CSF-1) are generated by proteolytic cleavage of membrane-bound glycoprotein precursors. Alternatively spliced transcripts of the human CSF-1 gene encode at least two different transmembrane precursors that are differentially processed in mammalian expression systems. The larger precursor rapidly undergoes proteolysis to yield the secreted growth factor and does not give rise to forms of CSF-1 detected on the cell surface. By contrast, the smaller human CSF-1 precursor is stably expressed on the plasma membrane where it is inefficiently cleaved to release a soluble molecule. To determine whether the smaller precursor is biologically active on the cell surface, mouse NIH-3T3 fibroblasts expressing the different forms of human CSF-1 were killed by chemical fixation and tested for their ability to support the proliferation of cells that require this growth factor. Only fixed cells expressing human CSF-1 precursors on their surface stimulated the growth in vitro of a murine macrophage cell line or normal mouse bone marrow-derived mononuclear phagocytes. The ability of these nonviable fibroblasts to induce the proliferation of CSF-1-dependent cells was not mediated by release of soluble growth factor, required direct contact with the target cells, and was blocked by neutralizing antiserum to CSF-1. These results demonstrate that the cell surface form of the human CSF-1 precursor is biologically active and indicate that plasma membrane- bound growth factors can functionally interact with receptor-bearing targets by direct cell-cell contact.

Sign in / Sign up

Export Citation Format

Share Document