The luteinizing hormone-releasing hormone (LHRH) receptor is a G protein-coupled receptor involved in the synthesis and release of pituitary gonadotropins and in the proliferation and apoptosis of pituitary cells. Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor that has a mitogenic effect on pituitary cells. In this study, we used the ␣T3 gonadotrope cell line as a model to characterize the IGF-1R signaling pathways and to investigate whether this receptor interacts with the LHRH cascade. We found that IGF-1 activated the IGF-1R, insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase, and Akt in a timedependent manner in ␣T3 cells. The MAPK (ERK1/2, p38, and JNK) pathways were only weakly activated by IGF-1. In contrast, LHRH strongly stimulated the MAPK pathways but had no effect on Akt activation. Cotreatment with IGF-1 and LHRH had various effects on these signaling pathways. 1) It strongly increased IGF-1-induced tyrosine phosphorylation of IRS-1 and IRS-1-associated phosphatidylinositol 3-kinase through activation of the epidermal growth factor receptor. 2) It had an additive effect on ERK1/2 activation without modifying the phosphorylation of p38 and JNK1/2. 3) It strongly reduced IGF-1 activation of Akt. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and cell cycle analysis revealed that, in addition to having an additive effect on ERK1/2 activation, cotreatment with IGF-1 and LHRH also had an additive effect on cell proliferation. The LHRH-induced inhibition of Akt stimulated by IGF-1 was completely blocked by Safingol, a protein kinase C (PKC) ␣-specific inhibitor, and by a dominant negative form of PKC␣. Finally, we showed that the inhibitory effect of LHRH on IGF-1-induced PKC␣-mediated Akt activation was associated with a marked reduction in Bad phosphorylation and a substantial decrease in the ability of IGF-1 to rescue ␣T3 cells from apoptosis induced by serum starvation. Our results demonstrate for the first time that several interactions take place between IGF-1 and LHRH receptors in gonadotrope cells. Luteinizing hormone-releasing hormone (LHRH)1 is a hypothalamic decapeptide, which plays a crucial role in normal reproductive function. In the pituitary, LHRH-I (mammalian LHRH) stimulates the synthesis and the release of the gonadotropins, LH and FSH, and promotes cell proliferation and apoptosis in pituitary cells (1, 2). The effects of LHRH-I are mediated by a cell surface receptor (LHRH-R) belonging to the G protein-coupled receptor superfamily (3, 4). LHRH-I binding to its cognate receptor leads to interaction of the receptor with heterotrimeric G proteins, including G q/11 . These G proteins in turn activate phospholipase C, leading to the production of diacylglycerol and the subsequent activation of protein kinase C (PKC) (5-9). Activation of PKC then leads to activation of downstream protein kinases belonging to the MAPK family (9 -15). Activation of LHRH-R also triggers calcium influx, resulting in an increase in intracellular c...