The regulation of retinoic acid receptor alpha (RAR␣) signal transduction has not been well characterized. In this study, we determined whether all-trans-retinoic acid (tRA) and follicle-stimulating hormone (FSH) modulate RAR␣ receptor subcellular localization, leading to changes in its transcriptional activity and protein expression in mouse Sertoli cell lines. We found that tRA induced the nuclear localization of RAR␣ within 30 min and that longer term exposure increased the receptor transcriptional activity and RAR␣ protein expression. Conversely, FSH suppressed the tRA-induced nuclear localization, transcriptional transactivation, and protein expression of RAR␣. Treatment with two different protein kinase A-selective antagonists reversed the inhibitory actions of FSH on tRA-dependent RAR␣ nuclear localization and transcriptional activity. These results are consistent with the involvement of protein kinase A in mediating the inhibitory effects of FSH. For the first time, we demonstrate a unique signaling convergence between the RAR␣ and the FSH-mediated signaling pathways, which may have significant implications in the testis because both are critical regulators of testis physiology.Vitamin A is required for various fundamental physiological processes including vertebrate development, cellular differentiation, vision, and reproduction (1, 2). The biologically active form of vitamin A is retinoic acid, which includes all-transretinoic acid (tRA) 1 and 9-cis-retinoic acid (3). The biological response of retinoic acid is mediated through two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors, each of which consists of three receptor subtypes, ␣, , and ␥ (4). Retinoid receptors are transcription factors that regulate the transcription of retinoic acid-responsive genes.Retinoid receptors belong to the larger superfamily of steroid/thyroid hormone receptors. Several members of this superfamily including the progesterone, the glucocorticoid, the estradiol, and the peroxisome proliferator-activated receptors are regulated at the level of nuclear trafficking (5-9). It was demonstrated that activation of cellular kinases increased the nuclear translocation and transcriptional activity of these receptors (8, 9). However, little is known about the regulation of RAR␣ subcellular localization and how this may affect its subsequent transcriptional activity. Previously, Tahayato et al. (10) reported that down-regulation of protein kinase C decreased RAR␣ nuclear localization and subsequent retinoic acid response element (RARE)-dependent transcriptional activity. In addition, although the regulation of nuclear trafficking was not examined, cAMP-dependent protein kinase (PKA) has been shown to decrease the transcriptional activity of RAR␣ and to inhibit the tRA-induced expression of all three retinoic acid receptor mRNAs in PC12, B16 melanoma, and F9 teratocarcinoma cells (11-13). In contrast, other reports indicate that the phosphorylation of RAR␣ on serine 369 by an overexpresse...