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Growth hormone-releasing hormone stimulates mitogen-activated protein kinase
C M Pombo1, J Zalvide, B D Gaylinn
1Department of Physiology, University of Santiago de Compostela School of Medicine, Spain. fscadigo@usc.es
Abstract:
GH-releasing hormone (GHRH) can induce proliferation of somatotroph cells. The pathway involving adenylyl cyclase/cAMP/protein kinase A pathway in its target cells seems to be important for this action, or at least it is deregulated in some somatotroph pituitary adenomas. We studied in this work whether GHRH can also stimulate mitogen-activated protein (MAP) kinase. GHRH can activate MAP kinase both in pituitary cells and in a cell line overexpressing the GHRH receptor. Although both protein kinase A and protein kinase C could activate MAP kinase in the CHO cell line studied, neither protein kinase A nor protein kinase C appears to be required for GHRH activation of MAP kinase in this system. However, sequestration of the betagamma-subunits of the G protein coupled to the receptor inhibits MAP kinase activation mediated by GHRH. This pathway also involves p21ras and a phosphatidylinositol 3-kinase, probably phosphatidylinositol 3-kinase-gamma. Despite the involvement of p21ras, the protein kinase Raf-1 is not hyperphosphorylated in response to GHRH, contrary to what usually occurs when the Ras-Raf-MAP kinase pathway is activated. In summary, this work describes for the first time the activation of MAP kinase by GHRH and outlines a path for this activation that is different from the cAMP-dependent mechanism that has been traditionally described as mediating the mitogenic actions of GHRH.
Insights
Growth hormone-releasing hormone (GHRH) activates mitogen-activated protein (MAP) kinase in pituitary cells. This novel pathway involves G-protein signaling, p21ras, and phosphatidylinositol 3-kinase, distinct from the traditional cAMP mechanism.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- Growth hormone-releasing hormone (GHRH) is known to induce somatotroph cell proliferation.
- The adenylyl cyclase/cAMP/protein kinase A pathway is implicated in GHRH's mitogenic actions and is deregulated in some pituitary adenomas.
Purpose of the Study:
- To investigate whether GHRH can stimulate mitogen-activated protein (MAP) kinase.
- To elucidate the signaling pathway mediating GHRH-induced MAP kinase activation.
Main Methods:
- Experiments were conducted in pituitary cells and a cell line overexpressing the GHRH receptor (CHO cells).
- Assessed MAP kinase activation in response to GHRH, protein kinase A, and protein kinase C.
- Investigated the role of G-protein beta-gamma subunits, p21ras, and phosphatidylinositol 3-kinase (PI3K) in the signaling pathway.
- Examined Raf-1 phosphorylation status following GHRH stimulation.
Main Results:
- GHRH activates MAP kinase in both pituitary cells and the GHRH receptor-overexpressing cell line.
- Neither protein kinase A nor protein kinase C is required for GHRH-mediated MAP kinase activation.
- G-protein beta-gamma subunit sequestration inhibits GHRH-induced MAP kinase activation.
- The pathway involves p21ras and phosphatidylinositol 3-kinase (likely PI3K-gamma).
- Raf-1 is not hyperphosphorylated in response to GHRH, unlike typical Ras-Raf-MAP kinase pathway activation.
Conclusions:
- This study demonstrates for the first time that GHRH activates MAP kinase.
- A novel signaling pathway for GHRH-induced MAP kinase activation is described, distinct from the established cAMP-dependent mechanism.
- The findings suggest a complex signaling cascade involving G-proteins, p21ras, and PI3K in mediating GHRH's effects on pituitary cells.