Growth Hormone-Releasing Hormone Stimulates Mitogen-Activated Protein Kinase*

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.

The growth hormone–releasing hormone (GHRH) antagonist JV-1-36 inhibits proliferation and survival of human ectopic endometriotic stromal cells (ESCs) and the T HESC cell line

“…Besides the cAMP pathway, GHRH R has been shown to act through the MAPK signaling cascade (28)(29)(30). Here, we report that JV-1-36 reduced p42/44 MAPK (ERK1/2) phosphorylation in T HESCs, in agreement with earlier findings showing ERK1/2 inhibition induced by GHRH antagonists in cancer cells (15,19,20).…”

“…The mitogen-activated protein kinase (MAPK) pathway, which includes ERK1/2, has been shown to be involved in GHRH-induced mitogenic signaling (28)(29)(30). We hypothesized that JV-1-36 would reduce ERK1/2 activity.…”

Hypothalamic Regulation of Anterior Pituitary Function

“…Activation of GHRHR increases intracellular calcium levels and stimulates adenylyl cyclase, which then increases intracellular cAMP concentrations [93]. GHRHR also activates pituitary phosphatidyl inositol and MAPK pathways [94].…”

Activation of Janus kinase/signal transducer and activator of transcription 3 pathway by growth hormone-releasing hormone

“…In addition, the binding of the GHRH to its receptor results to the activation of the MAPKs ERK1/2 [16,17].…”