Insulin-like growth factor I synergizes with interleukin 4 for hematopoietic cell proliferation independent of insulin receptor substrate expression

In the present study, we investigated the potential role of insulin-like gr owth factor I (IGF-I) receptor (IGF-IR) in cell proliferation by overexpres sing it in 32D myeloid progenitor cells. The overexpression of IGF-IR cause d the transfectants to proliferate in response to IGF-I in the absence of i nsulin receptor substrate (IRS) expression, The activation of overexpressed wild-type IGF-IR, but not that of an ATP-binding mutant of IGF-IR, resulte d in the increased tyrosine phosphorylation of several intracellular protei ns, including SHC, Src homology 2-containing inositol-5-phosphatase, protei n kinase C-delta, and Erk2, Grb2 association with SHC and mitogen-activated protein kinase (MAPK) activity was also enhanced in response to IGF-I stim ulation. Interestingly, the stimulation of the IGF-IR transfectants with in terleukin 4 (IL-4) also resulted in strong mitogenesis independent of IRS e xpression. Moreover, IGF-I and/or IL-4 induced long-term cell growth of the IGF-IR transfectants. IL-4 was able to synergize with IGF-I for DNA synthe sis, even in the parental 32D cells and a pro-B-cell line, Baf3, indicating the physiological importance of the two growth factors in hematopoietic ce ll proliferation. IL-4 stimulation of the IGF-IR transfectants resulted in enhanced tyrosine phosphorylation of SHC, Erk2, and signal transducer and a ctivator of transcription 6 (STAT6) proteins. Both IL-4 and IGF-I were able to induce c-myc early response gene expression, and this expression was ma ximal in the presence of both factors. Finally, we demonstrated that a MAPK kinase inhibitor was able to suppress mitogenesis of the IGF-IR transfecta nts in response to IGF-I and/or IL-4. Together, our results suggest that IL -4 synergizes with IGF-I for hematopoietic cell proliferation, likely throu gh cross talk between SHC/Grb2/MAPK and STAT6 pathways and through c-myc ge ne up-regulation.