TMEFF2

Official Full Name

transmembrane protein with EGF like and two follistatin like domains 2

Organism

Homo sapiens

GeneID

23671

Background

This gene encodes a member of the tomoregulin family of transmembrane proteins. This protein has been shown to function as both an oncogene and a tumor suppressor depending on the cellular context and may regulate prostate cancer cell invasion. Multiple soluble forms of this protein have been identified that arise from both an alternative splice variant and ectodomain shedding. Additionally, this gene has been found to be hypermethylated in multiple cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

Synonyms

TR; HPP1; TPEF; TR-2; TENB2; CT120.2;

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Detailed Information

The TMEFF2 gene, fully named Transmembrane Protein with EGF-Like and Two Follistatin-Like Domains 2, also known as Tomoregulin-1, is located on human chromosome 2q32.3. It encodes a member of the Tomoregulin family and belongs to type I single-pass transmembrane proteins. Structurally, its extracellular region contains one epidermal growth factor (EGF)-like domain and two follistatin-like domains, suggesting a role in intercellular signaling and interactions. Its intracellular segment is relatively short, implying that signal transduction likely depends on interaction with other membrane receptors or on proteolytic release of its extracellular domain. TMEFF2 expression is highly tissue-specific, with elevated levels in the central nervous system-particularly the hippocampus and brainstem-and in prostate tissue. The gene undergoes complex alternative splicing, producing multiple isoforms and adding functional diversity. Moreover, the extracellular domain can be proteolytically cleaved ("ectodomain shedding") to release a soluble form into the extracellular space, which may have distinct or even opposing biological functions compared to the full-length transmembrane form.

Figure 1. Protein architecture of TMEFF2, a transmembrane protein containing one EGF-like and two follistatin-like domains. (Masood M, et al., 2020)

Biological Significance

TMEFF2's biological functions are highly context-dependent, especially in cancer biology, where it exhibits both tumor-suppressive and tumor-promoting properties. This duality makes it a molecule of significant research interest. Under normal physiological conditions, TMEFF2 was first identified as a survival factor for hippocampal and midbrain dopaminergic neurons, suggesting a neurotrophic role in the nervous system. Its more prominent function lies in regulating cellular signaling pathways.

As a tumor suppressor, TMEFF2 can inhibit key proliferative and pro-survival pathways, including TGF-β signaling and the MAPK/ERK pathway, which are often aberrantly activated in various cancers. By antagonizing these pathways, TMEFF2 may restrict malignant proliferation and invasion.

Conversely, in certain cellular contexts, TMEFF2 can promote tumorigenesis. Its proteolytically shed soluble form has been shown to enhance cancer cell proliferation, likely through ERK1/2 phosphorylation, highlighting a functional reversal dependent on microenvironment, proteolytic processing, and co-receptor context.

TMEFF2 is also closely linked to epigenetic regulation. Hypermethylation of its promoter is frequently observed in colorectal cancer, prostate cancer, and gliomas, leading to loss of protein expression. This epigenetic silencing strongly supports its tumor suppressor role, and promoter methylation status may serve as a valuable diagnostic and prognostic biomarker.

Clinical Relevance

Clinically, TMEFF2 is significant as a potential biomarker and therapeutic target. Its tissue-specific expression in the prostate and nervous system, combined with frequent promoter hypermethylation in tumors, makes it a promising diagnostic marker. Detection of TMEFF2 methylation in circulating DNA from blood or urine is under investigation as a non-invasive method for early diagnosis or monitoring of colorectal and prostate cancers.

Therapeutically, TMEFF2's transmembrane localization and relative tumor-specific surface expression make it an attractive target for antibody-drug conjugates (ADCs) or other targeted therapies. Monoclonal antibodies recognizing its extracellular domain could deliver cytotoxic agents selectively to TMEFF2-expressing tumor cells, maximizing tumor killing while minimizing off-target effects.

However, its dual functional roles present challenges. In tumors with TMEFF2 silenced by hypermethylation, demethylating agents could restore its tumor-suppressive activity. Conversely, in tumors where TMEFF2 promotes proliferation, antibodies or small molecules may be required to block its function. Given its normal roles in the central nervous system, systemic targeting strategies must carefully consider potential neurotoxicity.

Overall, TMEFF2 is a complex, epigenetically regulated molecule with significant potential in tumor diagnostics and targeted therapy, though its clinical translation requires careful consideration of context-specific functions.

References

Lombardi DP, Geradts J, Foley JF, et al. Loss of KAI1 expression in the progression of colorectal cancer. Cancer Res. 1999;59(22):5724-5731.
Uchida T, Wada K, Akamatsu T, et al. A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells. Biochem Biophys Res Commun. 1999;266(2):593-602.
Masood M, Grimm S, El-Bahrawy M. TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease. Cancers (Basel). 2020 Dec 21;12(12):3862.

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