New perspectives of the molecular mechanisms to potentiate IGF signals

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In many cell types IGF-I has been shown to possess a variety of bioactivities. Despite the profuseness and diversity of these effects of IGFs, the in vitro biological effects of IGFs are relatively weak and often are not demonstrable except in the presence of other hormones or growth factors. These findings suggest that IGFs act as permissive factors to augment the signals or other factors. We have shown that in FRTL-5, a thyroid follicular cell line, TSH and IGF-I stimulate cell growth synergistically and cAMP pretreatment is essential for the potentiation of IGF-I-dependent DNA synthesis. In this cell line, cAMP pretreatment caused an increase in tyrosine kinase activity and tyrosine phosphorylation of intracellular proteins such as a 125-kDa protein (p125), which was well correlated with a cAMP-priming effect on potentiation of DNA synthesis induced by IGF-I.We recently found that the phosphotyrosyl p125 bound to a PI-3 kinase p85 regulatory subunit, and LY294002 (a PI-3 kinase inhi … More bitor) blocked the cAMP-priming effect. Taken together with the data that tyrosine kinase and PI-3 kinase activities are necessary for cAMP-dependent increases in Gl cyclins, our results suggest that CAMP stimulus recruit the quiescent cells into the cell cycle through cAMP-induced changes of tyrosine phosphorylation. On the other hand, we demonstrated that cAMP pretreatment potentiated IRS-2 and Shc tyrosine phosphorylation induced by IGF-I, although pretreatment with cAMP did not affect autophosphorylation of the IGF-I receptor. cAMP pretreatment increased Grb2 binding to IRS-2 and Shc, and MAP kinase activation induced by IGF-I was also enhanced by cAMP stimulus. Furthermore, cAMP pretreatment increased IRS-2 association with the PI-3 kinase p85 subunit, and IGF-I-induced PI-3 kinase activity bound to IRS-2 was enhanced by cAMP pretreatment. Finally, the presence of PD98059 (a MEK inhibitor) or LY294002 during IGF-I treatment abolished the cAMP-dependent augmentation of IGF-I dependent DNA synthesis. These results suggest that cAMP stimulus amplifies the IGF-I signals through cAMP-dependent potentiation of tyrosine phosphorylation of IGF-I receptor substrates. In conclusion, interaction between tropic hormone-dependent and IGF-I-dependent pathways leads to an augmentation of cell proliferation through the cAMP-dependent process of priming the cells to respond to IGF-I and amplification of IGF-I mitogenic activities. Less