Regulation of Cell proliferation by GM-CSF

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces various functions including the proliferation and differentiation of a broad rango of hematopoietic cells. We reported that at least two distinct pathways are involved in human GM-CSF receptor signaling both of which require the box 1 region of the common beta (betac) subunit. This region is essential for the activation of JAK2, which is necessary for all the biological functions of GM-CSF.Activation of JAK2 by GM-CSF leads to rapid tyrosine phosphorylation of cellular proteins, including the betac. However, the siguificance of the betac phosphorylation in regards to the regulation of signaling molecules and the expression of GM-CSF function is less well understood. Here we investigated the role of cytoplasmic tyrosine residues of the betac by using a series of betac mutants expressed in murine BA/F3 cells. A mutant betac with all eight cytoplasmic tyrosines converted to phenylalanine (Fall) activated JAK2, but not SHP-2, MAPK cascades, STAT5 or c-fos promoter in BA/F3 cells, nor did it effectively induce proliferation. Adding back each tyrosine to Fall revealed that Tyr577, Tyr612 and Tyr695 are involved in the activation of SHP-2, MAPK cascades and c-fos transcription, while every tyrosine, particularly Tyr612, Tyr695, Tyr750 and Tyr806, facilitated STAT5 activation. Impaired growth was also reatored, at least partly, by any of the tyrosines. These results provide evidence that betac tyrosines possess distinct yet overlapping functions to activate multiple signaling pathways induced by GM-CSF.