Endocrine Abstracts (2009) 20 P678

The MAPKinases ERK1/2 take centre stage in somatotroph physiopathology

Morgane Pertuit, David Romano, Anne Barlier, Alain Enjalbert & Corinne Gerard

CRN2M, UMR6231 CNRS, Marseille, France.

Somatotroph pituitary adenomas are characterized by unrestrained hormone secretion and cell proliferation alterations. In those tumors, the only mutation so far unequivocally identified is the gsp oncogene (Gsα protein gain of function mutation). Nethertheless, there is no clear difference in the clinical phenotypes of patients bearing tumor with the gsp oncogene (gsp+) or not (gsp−). In addition, an overexpression of the wild-type Gsα protein has been observed in a subset of gsp− adenomas. To apprehend the role of Gsα alterations in the initiation and progression of GH-secreting adenomas, we have recently developed doxycline-dependent Gsα expressing cell lines derived from the rat pituitary GH4C1 cells. Using these conditional cell lines, we show that induction of the expression of the gsp oncogene as well as overexpression of the wt Gsα protein, which both disrupt the cAMP pathway, induces a chronic activation of the MAPKinases ERK1/2 cascade. This ERK1/2 pathway upregulation is involved in the sustained activation of the human PRL and GH promoters observed in both cell lines. Our results are in close correlation with clinical observations and demonstrate how a slight overexpression of Gsα can cause physiological disorders similar to the gsp oncogene ones. We are currently investigating the molecular mechanims, downstream of Gsα, responsible for unrestrained ERK1/2 activity. In both cell lines, we show that the Src kinases are involved in sustained ERK1/2 activation. Moreover co-immunoprecipitation experiments suggest a direct recruitment of Src by Gsα. Src could in turn activate Ras and Rap1 which are both activated and contribute to ERK1/2 hyperactivation. Together, these results put forward a novel Gsα-Src-Ras/Rap1-ERK1/2 signaling pathway as a critical component in somatotroph physiopathology and could be relevant to develop new therapeutical molecules.

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