Identification and Characterization of TMEFF2, a Novel Survival Factor for Hippocampal and Mesencephalic Neurons

Horie, Masato; Mitsumoto, Yasuhide; Kyushiki, Hiroyuki; Kanemoto, Naohide; Watanabe, Akihito; Taniguchi, Yasushi; Nishino, Norikazu; Okamoto, Takashi; Kondo, Mari; Mori, Toyoki; Noguchi, Koichi; Nakamura, Yusuke; Takáhashi, Eiichi; Tanigami, Akira

doi:10.1006/geno.2000.6228

Cited by 73 publications

(85 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this respect, it has been reported that downregulation of TMEFF2 in androgen-independent prostate cancer xenografts, as well as growth inhibition induced by ectopic expression of TMEFF2 in androgen-independent prostate cancer cell lines (Gery et al 2002). Conversely, however, lower levels of TMEFF2 are found in multiple cancer tissues, especially in the malignant brain and colorectal samples, when compared with normal tissue (Horie et al 2000). These findings together with our results indicate a possible tissuedependent function of TMEFF2 in different human tumors.…”

Section: Discussionsupporting

confidence: 69%

“…It has been deduced to encode a 368 amino acid protein, which contains a predicted N-terminal signal peptide, extracellular domains consisting of an altered EGF-like repeat and two follistatin modules, and a transmembrane domain connected to a cytosolic tail with a putative G-proteinactivating motif. TMEFF2 is predominantly expressed in prostate and brain (Uchida et al 1999, Horie et al 2000, Liang et al 2000, Glynne-Jones et al 2001, Young et al 2001, Gery et al 2002 and has been implicated in cell signaling (Uchida et al 1999), neuronal cell survival (Horie et al 2000), and tumor suppression (Liang et al 2000, Young et al 2001, Gery et al 2002.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

Labeur¹,

Wölfel²,

Stalla³

et al. 2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

Labeur¹,

Wölfel²,

Stalla³

et al. 2015

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

show abstract

“…TMEFF2, a type I transmembrane protein with two follistatin and epidermal growth factor (EGF) domains, is expressed selectively in the adult brain and prostate (Horie et al, 2000; Liang et al, 2000), with elevated TMEFF2 expression in prostate cancer (PCa) cell lines and clinical samples (Glynne‐Jones et al, 2001; Gery et al, 2002; Afar et al, 2004). However, the role of TMEFF2 in PCa development and progression remains unclear, and TMEFF2 activity may depend on disease stage and/or post‐transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

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

Gaweł-Bęben

Ali

Ellis

et al. 2017

Cell Biology International

View full text Add to dashboard Cite

TMEFF2 is a type I transmembrane protein with two follistatin (FS) and one EGF‐like domain over‐expressed in prostate cancer; however its biological role in prostate cancer development and progression remains unclear, which may, at least in part, be explained by its proteolytic processing. The extracellular part of TMEFF2 (TMEFF2‐ECD) is cleaved by ADAM17 and the membrane‐retained fragment is further processed by the gamma‐secretase complex. TMEFF2 shedding is increased with cell crowding, a condition associated with the tumour microenvironment, which was mediated by oxidative stress signalling, requiring jun‐kinase (JNK) activation. Moreover, we have identified that TMEFF2 is also a novel substrate for other proteases implicated in prostate cancer, including two ADAMs (ADAM9 and ADAM12) and the type II transmembrane serine proteinases (TTSPs) matriptase‐1 and hepsin. Whereas cleavage by ADAM9 and ADAM12 generates previously identified TMEFF2‐ECD, proteolytic processing by matriptase‐1 and hepsin produced TMEFF2 fragments, composed of TMEFF2‐ECD or FS and/or EGF‐like domains as well as novel membrane retained fragments. Differential TMEFF2 processing from a single transmembrane protein may be a general mechanism to modulate transmembrane protein levels and domains, dependent on the repertoire of ADAMs or TTSPs expressed by the target cell.

show abstract

“…High expression of TMEFF1 was detected in only several cancer cell lines from different origins including prostate, breast and lung. This gene displays a high degree of homology with TMEFF2 (Horie et al, 2000: Glynne-Jones et al, 2001. Both TMEFF1 and TMEFF2 are expressed at high levels in the brain, implicating their importance in the function of the normal central nervous system.…”

Section: Discussionmentioning

confidence: 99%

TMEFF1 and brain tumors

et al. 2003

View full text Add to dashboard Cite

TMEFF1 is a novel transmembrane protein, containing two follisatin domains and an epidermal growth factorlike region. These structural domains suggest a role for TMEFF1 in growth factor signaling. TMEFF1 fused to enhanced green fluorescent protein revealed that TMEFF1 is expressed on the cell membrane. Northern analysis of normal human tissue showed that TMEFF1 is predominantly expressed in the brain. Study of cancer cell lines from different tissues including the brain, demonstrated moderate to low levels of TMEFF1 in most of these transformed cell lines. Furthermore, quantitative real-time RT-PCR analysis of 54 brain tumors showed that most of these tumors (96%) had lower levels of TMEFF1 expression than normal brain tissue. Interestingly, ectopic expression of TMEFF1 in brain cancer cells resulted in their growth inhibition. These data suggest that TMEFF1 may behave as a tumor suppressor gene in brain cancers.

show abstract

Identification and Characterization of TMEFF2, a Novel Survival Factor for Hippocampal and Mesencephalic Neurons

Cited by 73 publications

References 20 publications

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

TMEFF2 is an endogenous inhibitor of the CRH signal transduction pathway

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

TMEFF1 and brain tumors

Contact Info

Product

Resources

About