Ligand-independent and EGF receptor-supported transactivation: Lessons from β2-adrenergic receptor signalling

Drube, Sebastian; Stirnweiss, Jörg; Valkova, Christina; Liebmann, Claus

doi:10.1016/j.cellsig.2006.01.003

Cited by 57 publications

(42 citation statements)

References 37 publications

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“…The mechanism by which gonadotropin binding to its GPCRs triggers activation of the MEK/ERK pathway is still controversial. As suggested by previous workers (Pierce et al 2001, Kim et al 2002, Drube et al 2006, Evaul & Hammes 2008, it may be possible that gonadotropin binding to GPCRs in carp ovarian follicle cells activates the MEK/ERK pathway through trans-activation of EGFRs and further studies would require exploration of the actual mechanism of such trans-activation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of ovarian steroidogenesis in vitro by gonadotropin in common carp Cyprinus carpio: interaction between calcium- and adenylate cyclase-dependent pathways and involvement of ERK signaling cascade

Paul

Kundu²,

Pramanick³

et al. 2010

Journal of Molecular Endocrinology

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Multiple signal transduction pathways mediating gonadotropin-induced testosterone and 17b-estradiol (E 2 ) production were identified in carp ovarian theca and granulosa cells in short-term co-incubation. Inhibitors of voltage-sensitive calcium channels (VSCCs) and calmodulin attenuated human chorionic gonadotropin (HCG)-induced steroid production, whereas modulators of adenylate cyclase and protein kinase A (PKA) increased their production, indicating that both calcium-and PKA-dependent pathways are involved in the regulation of gonadotropin-induced steroidogenesis in carp ovary. Interactions between these two pathways are evident from the positive effect of elevated intracellular calcium on HCG-induced steroid production and the reduction of forskolin (FK)-and dibutyryl cAMP (dbcAMP)-induced steroidogenesis by inhibitors of VSCCs and calmodulin. In this study, we found the involvement of a third signaling pathway, a mitogen-activated protein kinase (MAP kinase), in the regulation of gonadal steroidogenesis in this fish. An antagonist of mitogen-activated protein kinase kinases 1/2 (MEK1/2; also known as MAP2K1/MAP2K2) markedly attenuated HCG-induced steroid production. Cells treated with HCG stimulated MEK1/2-dependent phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERKs1/2) in a concentration and time-dependent manner. Moreover, ERK1/2 activation in cells was mimicked by FK and dbcAMP suggesting that ERK1/2 transduce signal downstream of PKA in HCG-induced ovarian steroidogenesis. Evidence for presence of cross talk between calcium-dependent pathways and this MAP kinase cascade has been shown by demonstrating the inhibitory effects of verapamil and calmodulin on ERK1/2 activation after HCG stimulation. Our results suggest that activation of ERK1/2 by HCG as well as other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis in carp ovary.

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Section: Discussionmentioning

confidence: 99%

Regulation of ovarian steroidogenesis in vitro by gonadotropin in common carp Cyprinus carpio: interaction between calcium- and adenylate cyclase-dependent pathways and involvement of ERK signaling cascade

Paul

Kundu²,

Pramanick³

et al. 2010

Journal of Molecular Endocrinology

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“…In contrast, the ␤ 2 -adrenergic receptor activates the EGFR in an extracellular, ligand-dependent, fashion in cardiac fibroblasts by stimulating matrix metalloproteinases (MMPs) to cleave membrane-bound EGFR ligand ectodomains (19). As another example, lysophosphatidic acid trans-activates the EGFR via MMPs and ectodomain shedding in COS cells (18) but through intracellular mechanisms in adrenal glomerulosa cells (21).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between G Protein-coupled and Epidermal Growth Factor Receptors Regulates Gonadotropin-mediated Steroidogenesis in Leydig Cells

Evaul

Hammes

2008

Journal of Biological Chemistry

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Gonadal steroid production is stimulated by gonadotropin binding to G protein-coupled receptors (GPCRs). Although GPCR-mediated increases in intracellular cAMP are known regulators of steroidogenesis, the roles of other signaling pathways in mediating steroid production are not well characterized. Recent studies suggest that luteinizing hormone (LH) receptor activation leads to trans-activation of epidermal growth factor (EGF) receptors in the testes and ovary. This pathway is critical for LH-induced steroid production in ovarian follicles, probably through matrix metalloproteinase (MMP)-mediated release of EGF receptor (EGFR) binding ectodomains. Here we examined LH and EGF receptor crosstalk in testicular steroidogenesis using mouse MLTC-1 Leydig cells. We demonstrated that, similar to the ovary, trans-activation of the EGF receptor was critical for gonadotropin-induced steroid production in Leydig cells. LH-induced increases in cAMP and cAMP-dependent protein kinase (PKA) activity mediated trans-activation of the EGF receptor and subsequent mitogen-activated protein kinase (MAPK) activation, ultimately leading to StAR phosphorylation and mitochondrial translocation. Steroidogenesis in Leydig cells was unaffected by MMP inhibitors, suggesting that cAMP and PKA trans-activated EGF receptors in an intracellular fashion. Interestingly, although cAMP was always needed for steroidogenesis, the EGFR/MAPK pathway was activated and necessary only for early (30 -60 min), but not late (120 min or more), LH-induced steroidogenesis in vitro. In contrast, 36-h EGF receptor inhibition in vivo significantly reduced serum testosterone levels in male mice, demonstrating the physiologic importance of this cross-talk. These results suggest that GPCR-EGF receptor cross-talk is a conserved regulator of gonadotropin-induced steroidogenesis in the gonads, although the mechanisms of EGF receptor trans-activation may vary.

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“…The mechanism by which gonadotropin binding to its GPCRs triggers activation of the MEK/ERK pathway is still controversial. As suggested previously (Pierce et al 2001, Kim et al 2002, Drube et al 2006, Evaul & Hammes 2008, it may be possible that gonadotropin binding to GPCRs in mouse endometrium activates the MEK/ERK pathway through transactivation of EGFRs and further studies would need to explore the actual mechanism of such transactivation.…”

Section: Discussionmentioning

confidence: 99%

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

Kundu

Pramanick

Paul

et al. 2012

Journal of Endocrinology

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In mouse uterus, at the late diestrus stage LH binding sites have previously been described. The aim of our study was to confirm the existence of LH receptor (Lhr (Lhcgr)) mRNA and its protein in mouse endometrium. Endometrium at all stages of the estrous cycle contained Lhr mRNA, essentially identical to that found in mouse ovary. Endometrium also contained a 72 kDa immunoreactive receptor protein that bound to mouse anti-LHR antibody in western blot. Both receptor mRNA and protein were maximally expressed in the endometrium at metestrus and LH caused a significant increase in their expression levels. Endometrium also contained 3b-hydroxy steroid dehydrogenase (3b-hsd) mRNA and 3b-HSD protein. LH addition elevated their expression and activity as evident from increased conversion of labeled pregnenolone to progesterone (P 4 ) and de novo P 4 synthesis. LH-induced endometrial P 4 synthesis is mediated through expression of steroidogenic acute regulatory (Star) gene. Results demonstrated that LH-induced P 4 synthesis in endometrium is possibly mediated through the cAMP pathway. Involvement of a MAPK pathway was also evident. Gonadotropin-stimulated endometrial P 4 synthesis was markedly attenuated by an antagonist of MEK1/2, PD98059. LH-stimulated MEK1/2-dependent phosphorylation of ERK1/2 in a concentration-and time-dependant manner in cultured endometrial tissues. Moreover, involvement of cAMP in LH-stimulated activation of ERK1/2 was also evident. It is therefore possible that the major signaling pathways regulating endometrial steroidogenesis in mouse, including the adenylate cyclase and MAP kinase pathways, converge at a point distal to activation of protein kinase A and ERK1/2.

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Ligand-independent and EGF receptor-supported transactivation: Lessons from β2-adrenergic receptor signalling

Cited by 57 publications

References 37 publications

Regulation of ovarian steroidogenesis in vitro by gonadotropin in common carp Cyprinus carpio: interaction between calcium- and adenylate cyclase-dependent pathways and involvement of ERK signaling cascade

Regulation of ovarian steroidogenesis in vitro by gonadotropin in common carp Cyprinus carpio: interaction between calcium- and adenylate cyclase-dependent pathways and involvement of ERK signaling cascade

Cross-talk between G Protein-coupled and Epidermal Growth Factor Receptors Regulates Gonadotropin-mediated Steroidogenesis in Leydig Cells

Expression of LH receptor in nonpregnant mouse endometrium: LH induction of 3β-HSD and de novo synthesis of progesterone

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