TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

Abstract

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.

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

“…The FS domains of TMEFF2 also regulate corticotropine‐releasing hormone (CRH) signalling in corticotrope cells, where the production of cAMP, CREB and expression of pro‐opiomelanocortin was inhibited, resulting in decreased cell proliferation (Labeur et al, 2015). On the other hand, growth‐promoting activity of soluble TMEFF2 has been described (Horie et al, 2000; Ali and Knäuper, 2007; Chen et al, 2011a; Chen and Ruiz‐Echevarría, 2013), suggesting that this may be cell type dependent and potentially regulated by the pattern of ADAM and TTSP expression as well as by the growth factors present in the extracellular environment.…”

“…Soluble TMEFF2 fragments containing FS-domains generated by proteolysis likely modify PDGF-AA growth factor signalling, where PDGF-AA-TMEFF2 complexes modify signalling through PDGFRa, thus full length TMEFF2 or soluble FS-domain containing TMEFF2 fragments may block PDGF-AA signalling (Lin et al, 2011). The FS domains of TMEFF2 also regulate corticotropine-releasing hormone (CRH) signalling in corticotrope cells, where the production of cAMP, CREB and expression of pro-opiomelanocortin was inhibited, resulting in decreased cell proliferation (Labeur et al, 2015). On the other hand, growth-promoting activity of soluble TMEFF2 has been described (Horie et al, 2000;Ali and Kn€ auper, 2007;Chen et al, 2011a;Chen and Ruiz-Echevarr ıa, 2013), suggesting that this may be cell type dependent and potentially regulated by the pattern of ADAM and TTSP expression as well as by the growth factors present in the extracellular environment.…”

The MAPK Pathway-Based Drug Therapeutic Targets in Pituitary Adenomas

“…RA has antiproliferative effect in corticotroph cell, and long-term treatment with RA has some clinical efficacy in patients with Cushing's disease (77). The mechanism of RA anti-tumor effects is shown with the expression of TMEFF2 (transmembrane protein with EGF-like and two follistatin-likedomains) that inhibits phosphorylation of AKT and ERK1/2 (31). TMEFF2 is significantly downregulated in corticotropinomas relative to control tissues, which suggests that TMEFF2 might be a tumor suppressor.…”

“…TMEFF2 is significantly downregulated in corticotropinomas relative to control tissues, which suggests that TMEFF2 might be a tumor suppressor. Silence of TMEFF2 in pituitary corticotroph cell line AtT20 promotes cell proliferation, while over-expression of TMEFF2 inhibits cell proliferation (31). Thus, TMEFF2 is a potential therapeutic target for ACTH-secreting adenomas.…”

<p>TMEFF2 inhibits pancreatic cancer cells proliferation, migration, and invasion by suppressing phosphorylation of the MAPK signaling pathway</p>

“…TMEFF2, a novel member of the EGF-like protein family, was found to possess the characteristics of tumor suppressor in recent years because it inhibited proliferation of tumor cells in vitro and growth of tumors in nude mice 8,9. TMEFF2 is a transmembrane protein with EGF-like and two follistatin-like domains 10.…”