TMEFF2 explained
The Transmembrane protein with an EGF-like and two follistatin-like domains 2 (TMEFF2) gene is located on chromosome 2q32-q33 and encodes a 374-residue long single polypeptide, type-I transmembrane proteoglycan.[1] According to the HUGO gene nomenclature committee, the aliases of TMEFF2 include, HPP1, Tomoregulin (TR), Transmembrane protein TENB2 (TENB2), Cancer/testis antigen family 120, member 2 (CT120.2) and Transmembrane protein containing EGF and follistatin domains (TPEF). TMEFF2 was identified and characterized by at least five independent groups within the time span of approximately a year.
TMEFF2 is proteolytically shed from the cell surface.[2] The reported functions of TMEFF2 span across a wide range of physiological and pathological spectra including metabolism, neuroprotection, apoptosis, embryonic development, onco-suppression and endocrine function. TMEFF2 promoter and its 5′-upstream CpG island are methylated in a number of cancers. An inverse correlation between TMEFF2 methylation and the stage, response to therapy and survival outcome has been observed.[1] The detection of methylated free-circulating TMEFF2 DNA has been suggested as a potential diagnostic tool for colorectal cancer. The TMEFF2 downregulation signature equals and sometimes outperforms the Gleason and pathological scores in prostate cancer. TMEFF2 is downregulated in glioma and cotricotropinomas, and it impairs the production of adrenocorticotropic hormone in glioma cells. Through binding the amyloid β protein, its precursor and derivatives, TMEFF2 provides neuroprotection in Alzheimer's disease.[2]
TMEFF2 is a multidomain protein with its N-terminus harbouring a signal peptide followed by two follistatin-like domains, an EGF (epidermal growth factor)-like domain, a transmembrane portion and a short intracellular domain.[1] The EGF-like domain of TMEFF2 appears to be functionally ineffective because of the substitution of a crucial arginine residue (Arg39) with histidine, whereas the follistatin-like domains are reported to be crucial for the relevant functions of TMEFF2 .[3] [4]
Further reading
- Masood M, Grimm S, El-Bahrawy M, Yagüe E . TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease . Cancers . 12. 12 . 3862 . December 2020 . 33371267 . 10.3390/cancers12123862 . 7766544 . free .
- Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
- Uchida T, Wada K, Akamatsu T, Yonezawa M, Noguchi H, Mizoguchi A, Kasuga M, Sakamoto C . A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells . Biochemical and Biophysical Research Communications . 266 . 2 . 593–602 . December 1999 . 10600548 . 10.1006/bbrc.1999.1873 .
- Liang G, Robertson KD, Talmadge C, Sumegi J, Jones PA . The gene for a novel transmembrane protein containing epidermal growth factor and follistatin domains is frequently hypermethylated in human tumor cells . Cancer Research . 60 . 17 . 4907–12 . September 2000 . 10987305 .
- Young J, Biden KG, Simms LA, Huggard P, Karamatic R, Eyre HJ, Sutherland GR, Herath N, Barker M, Anderson GJ, Fitzpatrick DR, Ramm GA, Jass JR, Leggett BA . Grant Robert Sutherland . HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers . Proceedings of the National Academy of Sciences of the United States of America . 98 . 1 . 265–70 . January 2001 . 11120884 . 14579 . 10.1073/pnas.011415298 . free .
- Glynne-Jones E, Harper ME, Seery LT, James R, Anglin I, Morgan HE, Taylor KM, Gee JM, Nicholson RI . TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence . International Journal of Cancer . 94 . 2 . 178–84 . October 2001 . 11668495 . 10.1002/ijc.1450 . 22411392 . free .
- Shibata DM, Sato F, Mori Y, Perry K, Yin J, Wang S, Xu Y, Olaru A, Selaru F, Spring K, Young J, Abraham JM, Meltzer SJ . Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas . Cancer Research . 62 . 20 . 5637–40 . October 2002 . 12384516 .
- Sato F, Shibata D, Harpaz N, Xu Y, Yin J, Mori Y, Wang S, Olaru A, Deacu E, Selaru FM, Kimos MC, Hytiroglou P, Young J, Leggett B, Gazdar AF, Toyooka S, Abraham JM, Meltzer SJ . Aberrant methylation of the HPP1 gene in ulcerative colitis-associated colorectal carcinoma . Cancer Research . 62 . 23 . 6820–2 . December 2002 . 12460892 .
- Gery S, Koeffler HP . Repression of the TMEFF2 promoter by c-Myc . Journal of Molecular Biology . 328 . 5 . 977–83 . May 2003 . 12729735 . 10.1016/S0022-2836(03)00404-2 .
- Sabbioni S, Miotto E, Veronese A, Sattin E, Gramantieri L, Bolondi L, Calin GA, Gafà R, Lanza G, Carli G, Ferrazzi E, Feo C, Liboni A, Gullini S, Negrini M . Multigene methylation analysis of gastrointestinal tumors: TPEF emerges as a frequent tumor-specific aberrantly methylated marker that can be detected in peripheral blood . Molecular Diagnosis . 7 . 3–4 . 201–7 . 2004 . 15068392 . 10.2165/00066982-200307030-00010 .
- Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–24 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
- Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y, Olaru A, Wang S, Mori Y, Deacu E, Hamilton J, Kan T, Krasna MJ, Beer DG, Pepe MS, Abraham JM, Feng Z, Schmiegel W, Greenwald BD, Meltzer SJ . Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk . Oncogene . 24 . 25 . 4138–48 . June 2005 . 15824739 . 10.1038/sj.onc.1208598 . free .
- Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, Wakamatsu A, Kimura K, Sakamoto K, Hatano N, Kawai Y, Ishii S, Saito K, Kojima S, Sugiyama T, Ono T, Okano K, Yoshikawa Y, Aotsuka S, Sasaki N, Hattori A, Okumura K, Nagai K, Sugano S, Isogai T . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries . DNA Research . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
Notes and References
- Masood M, Grimm S, El-Bahrawy M, Yagüe E . TMEFF2: A Transmembrane Proteoglycan with Multifaceted Actions in Cancer and Disease . Cancers . 12. 12 . 3862 . December 2020 . 33371267 . 10.3390/cancers12123862 . 7766544 . free .
- Web site: TMEFF2 Encyclopedia MDPI .
- Horie M, Mitsumoto Y, Kyushiki H, Kanemoto N, Watanabe A, Taniguchi Y, Nishino N, Okamoto T, Kondo M, Mori T, Noguchi K, Nakamura Y, Takahashi EI, Tanigami A . Identification and characterization of TMEFF2, a novel survival factor for hippocampal and mesencephalic neurons . Genomics . 67 . 2 . 146–52 . July 2000 . 10903839 . 10.1006/geno.2000.6228 .
- Web site: Entrez Gene: TMEFF2 transmembrane protein with EGF-like and two follistatin-like domains 2.