Uncoupling of the proliferation and differentiation signals mediated by the murine macrophage colony-stimulating factor receptor expressed in myeloid FDC-P1 cells.
The macrophage colony-stimulating factor (M-CSF) regulates proliferation and differentiation of cells belonging to the monocytic lineage. We have investigated the nature and origin of the proliferation and differentiation signals derived from the M-CSF receptor (Fms) by mutating Fms at the four tyrosine autophosphorylation sites and examining their biological effects in an FDC-P1 clone. Wild-type Fms stimulated both growth and differentiation of FDC-P1 cells in response to M-CSF stimulation. In contrast, both proliferation and differentiation were differentially disrupted by mutations affecting the four tyrosine autophosphorylation sites. These analyses revealed that: (a) none of the four autophosphorylation sites studied (Y697, Y706, Y721, and Y807) were essential for M-CSF-dependent proliferation of the FDC-P1 clone; (b) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, were not necessary for differentiation, but their presence augmented this process; (c) mutation of the Y807 site totally abrogated the differentiation of the FDC-P1 clone and simultaneously increased the rate of M-CSF-dependent proliferation; and (d) conversely, increasing the intracellular cAMP level blocked the growth signal in the FDC-P1 clone but had no effect on differentiation. These results suggest that autophosphorylation of Fms at the Y807 site controls the balance between signals for growth and differentiation.
Bourette
R P
RP
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Myles
G M
GM
Carlberg
K
K
Chen
A R
AR
Rohrschneider
L R
LR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D019000:Phosphotyrosine; D011499:Protein Processing, Post-Translational; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000502:physiology
D011993:Recombinant Fusion Proteins; D005576:Colforsin; D019000:Phosphotyrosine; D014443:Tyrosine; D016173:Macrophage Colony-Stimulating Factor; D000242:Cyclic AMP; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015232:Dinoprostone