Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate proliferation, dierentiation and apoptosis of target cells. Receptors for these cytokines consist of a cytokinespeci®c a subunit and a common shared bc subunit. Tyrosine phosphorylation of the bc is thought to play a critical role in mediating signal transduction events. We have examined the eect of mutation of bc tyrosines on the activation of multiple signal transduction pathways. Activation of protein kinase B (PKB) required JAK2 and was inhibited by dominant-negative phosphatidylinositol 3-kinase (P13K). Overexpression of JAK2 was sucient to activate both protein kinase B (PKB) and extracellular regulated kinase-1 (ERK1). Tyrosine 577 and 612 were found to be critical for the activation of PKB and ERK1, but not activation of STAT transcription factors. Activation of both PKB and ERK have been implicated in the regulation of proliferation and apoptosis. We generated GM-CSFR stable cell lines expressing receptor mutants to evaluate their eect on these processes. Activation of both PKB and ERK was perturbed, while STAT activation remained unaected. Tyrosines 577 and 612 were necessary for optimal proliferation, however, mutation of these tyrosine residues did not aect GM-CSF mediated rescue from apoptosis. These data demonstrate that while phosphorylation of bc tyrosine residues 577 and 612 are important for optimal cell proliferation, rescue from apoptosis can be mediated by alternative signalling routes apparently independent of PKB or ERK activation.