GPCR/EGFR Cross Talk Is Conserved in Gonadal and Adrenal Steroidogenesis but Is Uniquely Regulated by Matrix Metalloproteinases 2 and 9 in the Ovary
GPCR/EGFR Cross Talk Is Conserved in Gonadal and Adrenal Steroidogenesis but Is Uniquely Regulated by Matrix Metalloproteinases 2 and 9 in the Ovary
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DOI：
10.1210/me.2010-0410
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发表时间：
2011-06-01
影响因子：
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通讯作者：
Hammes, Stephen R.
中科院分区：
文献类型：
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作者：
Carbajal, Liliana;Biswas, Anindita;Hammes, Stephen R.
先前的研究表明，G蛋白偶联LH受体和表皮生长因子受体（EGFR）之间的串扰对于LH诱导的卵巢卵泡和睾丸间质细胞的类固醇生成至关重要。在这里，我们证明G蛋白偶联受体(GPCR)/EGFR串扰也是acth诱导的Y1肾上腺细胞类固醇生成所必需的。此外，我们证实了从GPCR到Erk激活的信号通路在所有三种类固醇生成组织中都是保守的。ACTH或LH诱导G α (s)，导致cAMP升高和蛋白激酶A激活。然后cAMP/蛋白激酶A触发EGFR反式激活，促进Erk信号传导和随后的类固醇生成。有趣的是，尽管EGFR反式激活在所有三种组织中都是保守的，但调节这种受体串扰的具体机制不同。ACTH和LH分别在肾上腺和性腺细胞中触发基质金属蛋白酶（MMP）介导的EGFR配体释放。然而，这种细胞外的、依赖配体的EGFR反激活只需要在卵巢卵泡中lh诱导的类固醇生成，这反映了卵巢类固醇生成的细胞-细胞串扰的独特需求。此外，MMP2和MMP9似乎调节了lh诱导的小鼠卵巢卵泡类固醇生成，因为一种特异性的MMP2/9抑制剂以及MMP2/9抑制剂强力霉素在体外抑制lh诱导的卵泡类固醇生成。值得注意的是，尽管EGFR或MMP抑制对雌性小鼠的发情周期影响最小，但它们在体内对LHR过度刺激的反应中减弱了卵巢甾体生成。这些结果可能与EGFR抑制剂在各种癌症和多囊卵巢综合征中的使用有关，其中过量的lh驱动的卵巢雄激素产生可能通过抑制MMP2/9来控制。（分子内分泌学25:1055-1065,2011）
Previous work has demonstrated that cross talk between G protein-coupled LH receptors and epidermal growth factor receptors (EGFR) is essential for LH-induced steroid production in ovarian follicles and testicular Leydig cells. Here we demonstrate that G protein-coupled receptor (GPCR)/EGFR cross talk is also required for ACTH-induced steroidogenesis in Y1 adrenal cells. Moreover, we confirm that the signaling pathway from GPCR to Erk activation is conserved in all three steroidogenic tissues. ACTH or LH induces G alpha(s), resulting in elevated cAMP and protein kinase A activation. cAMP/protein kinase A then triggers EGFR trans-activation, which promotes Erk signaling and subsequent steroidogenesis. Interestingly, although EGFR trans-activation is conserved in all three tissues, the specific mechanisms regulating this receptor cross talk differ. ACTH and LH trigger matrix metalloproteinase (MMP)-mediated release of EGFR ligands in adrenal and gonadal cells, respectively. However, this extracellular, ligand-dependent EGFR transactivation is required only for LH-induced steroidogenesis in ovarian follicles, reflecting the unique requirement of cell-cell cross talk for ovarian steroid production. Furthermore, MMP2 and MMP9 appear to regulate LH-induced steroidogenesis in mouse ovarian follicles, because a specific MMP2/9 inhibitor as well as the MMP2/9 inhibitor doxycycline suppress LH-induced follicular steroid production in vitro. Notably, although EGFR or MMP inhibition minimally affects estrous cycling in female mice, they attenuate ovarian steroidogenesis in response to LHR overstimulation in vivo. These results may have implications with regard to EGFR inhibitor use in various cancers as well as in polycystic ovarian syndrome, where excess LH-driven ovarian androgen production might be controlled by MMP2/9 inhibition. (Molecular Endocrinology 25: 1055-1065, 2011)