Endocrine Abstracts

The Ras/Raf/MEK/ERK is a conserved signalling pathway involved in the control of fundamental cellular processes. Despite extensive research, how this pathway can process a myriad of diverse extracellular inputs into specific biological outcomes is not fully understood. Particularly, the role of this pathway in neuroendocrine tumoral cells remains unclear.

We have previously shown that the ERK1/2 pathway is an integrative point in the control of the pituitary function exerted by various extracellular signals. Moreover we established that the cross talk between the cAMP pathway and the ERK cascade is crucial for the fine regulation of hormonal transcription. In somatotroph tumoral cells, we have shown that the gsp-oncogene (due to an activating mutation of Gsα) induced a sustained activity of ERK1/2 that is involved in the hormonal promoter activation through the GTPases Ras and Rap1. Recently, using the FRET-based biosensors of ERK activity (EKAR), we established that both the EGF receptor and the GPCR coupled to the cAMP-pathway tightly control the spatiotemporal dynamic of activated ERK with different magnitude and duration through the specific recruitment of Ras and Rap1. Moreover, in human pituitary tumors, Dworakowska et al. showed that raf/MEK/ERK pathway is up-regulated.

It is well known that octreotide exerts an inhibitory effect on hormonal secretion of pituitary and neuroendocrine cells through the cAMP pathway. A slight but significant inhibitory effect was also observed on tumoral growth and cell proliferation but the signalling mechamisms underlying such an antiproliferative effect remains unclear. Using a somato-lactotroph cell line expressing the sst2 receptor, we identified an opposite effect of ligand-independent and octreotide-dependent sst2 activity on the ERK1/2 activity. The molecular mechamisms involved in SST2-dependent ERK activity is currently under investigation.