A critical role for the cytoplasmic domain of the granulocyte-macrophage colony-stimulating factor alpha receptor in mediating cell growth.
The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor is composed of an alpha subunit which binds GM-CSF and a beta subunit which allows for high affinity binding. To investigate the role of the short cytoplasmic tail (54 amino acids) of the alpha receptor in mediating signal transduction and in controlling cell growth, we placed a stop codon after the alpha receptor transmembrane domain and expressed this receptor in murine Ba/F3 cells. Unlike the complete alpha subunit, this shortened receptor was unable to stimulate protein phosphorylation or mediate entry into the cell cycle. By comparing Ba/F3 cells expressing the alpha and beta receptors with those expressing the alpha or the terminated alpha receptor, we have been able to correlate specific GM-CSF-induced events with cell cycle commitment. We find that cell growth is correlated with prolonged increases in the cell levels of c-myc, pim-1, and cyclin D2 mRNAs, but not with changes in either immediate early genes or mitogen-activated protein kinase phosphorylation. This suggests that additional signal transduction pathways not mediated by known phosphoproteins are activated by GM-CSF. Since the beta receptor is shared by human interleukins 3 and 5, our data suggest that the specificity of response to GM-CSF is mediated in part by the short cytoplasmic tail of the alpha receptor subunit.
Division of Hematology/Oncology, University of Alabama, Birmingham 35294.
A
A
Polotskaya
Y
Y
Zhao
M L
ML
Lilly
A S
AS
Kraft
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D056742:Cyclin D2; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003593:Cytoplasm; D005786:Gene Expression Regulation / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015202:Protein Engineering; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
C080336:CCND2 protein, human; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1