Intracellular Signaling Pathways Mediated by the Gonadotropin-Releasing Hormone (GnRH) Receptor

Kraus, Sarah; Naor, Zvi; Seger, Rony

doi:10.1016/s0188-4409(01)00331-9

Cited by 178 publications

(113 citation statements)

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“…Many of the cellular actions of GnRH are dependent on the phosphorylation and activation of MAPKs, including ERK1/2, c-Jun N-terminal kinase, and p38 MAPK, through diverse signaling pathways (31,32). Earlier studies in ␣T3-1 pituitary gonadotropes gave conflicting results on the involvement of the EGF-R in mediating the activation of ERK1/2 by GnRH (33, 34).…”

Section: Discussionmentioning

confidence: 99%

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Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Shah

Farshori

Catt

2004

Journal of Biological Chemistry

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Numerous external stimuli, including G protein-coupled receptor agonists, cytokines, growth factors, and steroids activate mitogen-activated protein kinases (MAPKs) through phosphorylation of the epidermal growth factor receptor (EGF-R). In immortalized hypothalamic neurons (GT1-7 cells), agonist binding to the gonadotropin-releasing hormone receptor (GnRH-R) causes phosphorylation of MAPKs that is mediated by protein kinase C (PKC)-dependent transactivation of the EGF-R. An analysis of the mechanisms involved in this process showed that GnRH stimulation of GT1-7 cells causes release/shedding of the soluble ligand, heparin binding epidermal growth factor (HB-EGF), as a consequence of metalloprotease activation. GnRH-induced phosphorylation of the EGF-R and, subsequently, of Shc, ERK1/2, and its dependent protein, p90 RSK-1 (p90 ribosomal S6 kinase 1 or RSK-1), was abolished by metalloprotease inhibition. Similarly, blockade of the effect of HB-EGF with the selective inhibitor CRM197 or a neutralizing antibody attenuated signals generated by GnRH and phorbol 12-myristate 13-acetate, but not those stimulated by EGF. In contrast, phosphorylation of the EGF-R, Shc, and ERK1/2 by EGF and HB-EGF was independent of PKC and metalloprotease activity. The signaling characteristics of HB-EGF closely resembled those of GnRH and EGF in terms of the phosphorylation of EGF-R, Shc, ERK1/2, and RSK-1 as well as the nuclear translocation of RSK-1. However, neither the selective Src kinase inhibitor PP2 nor the overexpression of negative regulatory Src kinase and dominant negative Pyk2 had any effect on HB-EGF-induced responses. In contrast to GT1-7 cells, human embryonic kidney 293 cells expressing the GnRH-R did not exhibit metalloprotease induction and EGF-R transactivation during GnRH stimulation. These data indicate that the GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HB-EGF through PKC-dependent activation of metalloprotease(s) in neuronal GT1-7 cells.

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Section: Discussionmentioning

confidence: 99%

“…GnRH-induced ERK1/2 activation in pituitary gonadotropes is dependent on both PKC and calcium (31,53). However, in GT1-7 cells this process is primarily dependent on the activation of a multiprotein signaling complex consisting of PKC␣/⑀ and the non-receptor tyrosine kinases Src and Pyk2 (11).…”

Section: ϩ2mentioning

confidence: 99%

Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Shah

Farshori

Catt

2004

Journal of Biological Chemistry

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“…It is now clear that the pituitary LHRH receptor is coupled to a Gq/11 protein (Naor et al 1998, Kraus et al 2001. Phospholipase (PL) Cβ is the primary effector in the intracellular cascade of events triggered by LHRH; the generated second messengers inositol trisphosphate and diacylglycerol lead to the activation of protein kinase C and to the mobilization of intracellular pools of Ca 2+ (Naor et al 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Phospholipase (PL) Cβ is the primary effector in the intracellular cascade of events triggered by LHRH; the generated second messengers inositol trisphosphate and diacylglycerol lead to the activation of protein kinase C and to the mobilization of intracellular pools of Ca 2+ (Naor et al 1998). LHRH also activates PLA 2 , PLD, and the MAP kinase cascade, which provides an important link for the transmission of signals from the cell surface to the nucleus and plays a role in the regulation of gonadotropin transcription (Naor et al 1998, Kraus et al 2001.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression.

Moretti

Marelli²,

Groeninghen³

et al. 2003

Endocrine-Related Cancer

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Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.

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“…MAP kinases were shown to be activated by GPR54 in CHO cells (21). These transduction pathways are implicated in GnRH regulation of LH and FSH synthesis and secretion (23).…”

Section: Gpr54: a G-protein-coupled Receptor With Diverse Functionsmentioning

confidence: 99%

New insights in the genetics of isolated hypogonadotropic hypogonadism

Iovane

Aumas

Roux

2004

European Journal of Endocrinology

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Isolated gonadotropic deficiency or isolated hypogonadotropic hypogonadism is defined as a low sexual hormone secretion by the gonads associated with low LH and FSH plasma levels. Kallmann syndrome is defined as a congenital isolated gonadotropic deficiency associated with anosmia whereas the phenotype of the idiopathic form is limited to the gonadotropic axis. For several years, it has been known that mutations of the KAL-1 gene or loss-of-function mutations of GnRH receptor did not explain all familial cases of isolated gonadotropic deficiency with or without anosmia. Thus the existence of other genes playing a major role in the physiology of the gonadotropic axis was highly suggested. In 2003, fibroblast growth factor receptor 1 (FGFR1) and GPR54 were shown to be two of these genes. FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis. European Journal of Endocrinology 151 U83-U88

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Intracellular Signaling Pathways Mediated by the Gonadotropin-Releasing Hormone (GnRH) Receptor

Cited by 178 publications

References 98 publications

Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression.

New insights in the genetics of isolated hypogonadotropic hypogonadism

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