JB Review TMEPAI family: involvement in regulation of multiple signalling pathways Received March 28, 2018; accepted June 25, 2018; published online June 26, 2018 Susumu Itoh 1, * and Fumiko Itoh 2 1 Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan and 2 Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan *Susumu Itoh, Laboratory of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194- 8543, Japan. Tel: +81-42-721-1558, Fax: +81-42-721-1588, email: sitoh@ac.shoyaku.ac.jp The TMEPAI family, composed of TMEPAI and C18ORF1, is known to inhibit transforming growth factor-b (TGF-b) signalling via its competition for bind- ing of receptor-regulated Smad with Smad anchor for receptor activation. However, TMEPAI has also been reported to be involved in androgen receptor signalling, phosphatase and tensin homologue deleted on chromo- some 10 signalling, and formation of autophagosomes in addition to degradation of TbRI (TGF-b type I recep- tor) through lysosomes. Thus, TMEPAI seems to act as a regulator of multiple signalling pathways. A great deal of attention has already been paid to the relation- ship between the TMEPAI family and tumourigenicity. In this paper, therefore, we describe recent progresses in the understanding of how the TMEPAI family physio- logically contributes to cellular functions and diseases. Keywords: AR; C18ORF1; NEDD4; Smad; TGF-b: TMEPAI. TMEPAI, officially named prostate transmembrane protein, androgen induced-1 (PMEPA1), was origin- ally discovered as an androgen-induced gene in the prostate (1). Later on, comprehensive screening by DNA microarray analysis identified TMEPAI as a transforming growth factor-b (TGF-b)-induced gene (2). Other than androgen and TGF-b, growth factors including EGF (epithelial growth factor), hypoxia, and the mutant version of p53 S121F are known inducers of TMEPAI (35). We have already reported that TMEPAI inhibits TGF-b signalling, but not the sig- nalling of the TGF-b-related cytokine bone morpho- genetic protein (BMP), by means of the negative feedback mechanism owing to its competition for bind- ing of receptor-regulated Smad (R-Smad) with Smad anchor for receptor activation (SARA) (6). Like TMEPAI, the TMEPAI-related protein C18ORF1, of- ficially named low-density lipoprotein (LDL) receptor class A domain containing 4 (LDLRAD4), is also involved in the negative regulation of TGF-b signalling, despite its expression not being upregulated upon TGF-b stimulation (7). Thus, we have classified both TMEPAI and C18ORF1 into the TMEPAI family. Recently, TMEPAI has been demonstrated to play a role in the degradation of TGF-b type I receptor (TbRI or activin receptor-like kinase 5 [ALK5]) (8), formation of autophagosomes (9) and epithelial-mes- enchymal transition (EMT) (10) as well as in the con- trol of AR (androgen receptor) signalling (1113). These findings suggest that TMEPAI contributes to cellular homeostasis as a regulator of multiple sig- nalling pathways. Furthermore, it has been reported that because of its high expression in tumour tissues, the TMEPAI family is possibly involved in tu- mourigenicity (1, 3, 6, 1418). In this review, after briefly introducing TGF-b sig- nalling, we will focus on the negative regulation of TGF-b signalling by the TMEPAI family and on recent reports that the TMEPAI family acts as a regu- lator of multiple signalling pathways with respect to its function and diseases. TGF-b signalling The TGF-b family consists of 33 cytokines including TGF-bs, activins, nodal, BMP and growth and dif- ferentiation factors (GDFs) in human. Among the TGF-b family, TGF-b plays a pivotal role in various physiological activities including cell differentiation, apoptosis, cell migration, production of matrix pro- teins, angiogenesis, immunosuppression and tumour promotion in addition to anti-proliferative responsive- ness. At the early stage of tumourigenicity, TGF-b promotes cell growth inhibition, whereas at the late stage, tumour cells frequently escape from TGF-b- mediated growth arrest. Furthermore, TGF-b acceler- ates the metastatic activity of tumour cells because tu- mour cells acquire the ability of cell migration, EMT and production of enzymes that degrade the extracel- lular matrix upon TGF-b stimulation. Tumour cells that possess the ability to metastasize can occasionally secrete a large amount of TGF-b by themselves to fur- ther enhance their motility in an autocrine manner. Additionally, TGF-b serves a vital role in formation of the tumour microenvironment by enhancing angio- genesis, supplying nutrients and oxygen to tumour cells and aborting the immune surveillance by which cytotoxic T and NK cells attack tumour cells. Therefore, TGF-b possesses a dual response, evoking tumour suppression and oncogenic action in early- and late-stage tumours, respectively (1922). TGF-b, which forms a dimer (presumably a homo- dimer), binds to two molecules of TbRI and two mol- ecules of TbRII (TGF-b type II receptor), resulting in J. Biochem. 2018;164(3):195–204 doi:10.1093/jb/mvy059 ß The Author(s) 2018. Published by Oxford University Press on behalf of the Japanese Biochemical Society. 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