ausblenden:
Schlagwörter:
TMEFF2, CRH, Cushing's, POMC
Zusammenfassung:
TMEFF2 is a transmembrane protein with unknown function, containing an
altered epidermal growth factor (EGF)-like motif, two follistatin-like
domains, and a cytosolic tail with a putative G-protein-activating
motif. TMEFF2 is predominantly expressed in brain and prostate and has
been implicated in cell signaling, neuronal cell survival, and tumor
suppression. We found that expression of TMEFF2 in pituitary
corticotrope cells inhibits the effects of corticotropin-releasing
hormone (CRH) on the production of intracellular cAMP, and CREB, and
transcription of Pomc. Regulation of the activity of CRH by TMEFF2
requires neither the cytoplasmic tail nor the EGF domain, while deletion
of the follistatin modules abolishes the inhibitory function of TMEFF2.
Moreover, a soluble secreted protein containing the complete
extracellular domain is sufficient for inhibition of CRH signaling.
TMEFF2-induced inhibition depends on serum components. Furthermore,
TMEFF2 regulates the non-canonical activin/BMP4 signaling, PI3K, and
Ras/ERK1/2 pathways. Thus, TMEFF2 inhibits the CRH signaling pathway and
the PI3K/AKT and Ras/ERK1/2 pathways, contributing to a significant
inhibition of transcription of Pomc. We found that expression of TMEFF2
in human Cushing's adenoma is reduced when compared with normal human
pituitary, which may indicate that TMEFF2 acts as a tumor suppressor in
these adenomas. Furthermore, the overexpression of TMEFF2 decreased
proliferation of corticotrope cells. Our results indicate a potential
therapeutic use of TMEFF2 or factors that stimulate the activity of
TMEFF2 for the treatment of corticotrope tumors in order to reduce their
secretion of ACTH and proliferation.
