Analysis of signals and functions of the chimeric human granuloctye-macrophage colony-stimulating factor receptor in BA/F3 cells and transgenic mice

Receptors for GM-CSF, IL-3, and IL-5 are composed of two subunits: alpha, w hich is specific for each cytokine, and beta c, which is shared by all, Alt hough the role of pc in signal transduction has been extensively studied, t he role of the Lu subunit has remained to be clarified. To analyze the role of the human (h) GM-CSF receptor cu subunit, we constructed a chimeric rec eptor subunit composed of extracellular and transmembrane regions of alpha fused with the cytoplasmic region of beta c, designated alpha/beta, In BA/F 3 cells, chimeric receptor composed of alpha/beta,beta can transduce signal s for mitogen-activated protein kinase cascade activation and proliferation in response to hGM-CSF. Although phosphorylation of Jak1 but not of Jak2 o ccurred with stimulation of hGM-CSF, the dominant-negative Jak2 but not the dominant-negative Jak1 suppresses c-fos promoter activation, To determine whether the chimeric receptor alpha/beta,beta is functional in vivo, we dev eloped transgenic mice expressing the chimeric receptor alpha/beta,beta. Bo ne marrow cells from the transgenic mice expressing the alpha/beta,beta rec eptor form not only GM colonies but also various lineages of colonies in re sponse to GM-CSF. In addition, mast cells were produced when bone marrow ce lls of the transgenic mouse were cultured with hGM-CSF, Thus, it appears th at the cytoplasmic region of the alpha subunit is not required for hGM-CSF promoting activities, even in bone marrow cells.