Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling.
The colony-stimulating factor-1 receptor (CSF-1R) mediates its pleiotropic effects through the coupling of its ligand-activated tyrosine kinase to multiple intracellular effector proteins, whose combined actions determine the magnitude and specificity of the biological response. The interaction of cytoplasmic signalling molecules with CSF-1R is mediated in part by sequence motifs flanking sites of receptor tyrosine phosphorylation. Mutation of an autophosphorylation site at tyrosine 809 in the cytoplasmic domain of human CSF-1R does not significantly reduce its ligand-stimulated tyrosine kinase activity, binding to phosphatidylinositol 3-kinase, or induction of the immediate early response genes, c-fos and junB (ref.2). Unlike cells bearing wild-type receptors, mouse NIH3T3 cells expressing mutant CSF-1R(Phe 809) were unable to grow in serum-free medium containing human recombinant CSF-1 and did not form colonies in semi-solid medium in its presence. CSF-1 induction of c-myc messenger RNA in these cells was impaired, but enforced expression of an exogenous c-myc gene restored their ability to proliferate in response to the growth factor. These studies demonstrate a receptor-mediated bifurcation of intracellular signal transduction pathways during the immediate early response and assign a central role for c-myc in CSF-1-induced mitogenesis.
Roussel
M F
MF
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Cleveland
J L
JL
Shurtleff
S A
SA
Sherr
C J
CJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D016259:Genes, myc / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D009154:Mutation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D012190:Retroviridae; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor