Abstract
The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the “division of labor” paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene’s multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.
Highlights
Prostate transmembrane protein androgen induced 1 (PMEPA1) is classified as a type 1b transmembrane protein with luminal, membrane spanning and cytoplasmic domains [1]
TNheEDsoDlid4 lmineedreiparteesdentPs TthEeNkndoewgnradation was PMEPA1-b iniinndhteeirpbaiecttnTiodGnFea-nβntdsiitnghnecadolionntgtt:erdaDsilfitnfeetroseniAntidaRilcardetegesugtlhartaeiodknnaotoiwfonTnGm.FTe-cβhhsaeingsinsomallii.nd(gBl)binPyMePEMrPeEApP1rAei1ss-oeafnoartnmsdstPh(-Mea EaknPndAo1--wdd) n interaction and the dotteisdofolirnmesscoinntdriibcuatetsestothanedkrongoenwinndmepeencdheannt,isTmGF.-β(Bco)nPtrMollEedPAce1ll igsroowfothr.mAsll(t-haesaenfdind-din)gisnhibit TGF-β signaling: Disffugegreesnt tPiMalErPeAg1ugleanteioutniliozef tTheGsFpe-cβifisciigsonfaorlminsginboyrdPerMtoEnPaAvig1a-tae aanndddPriMve EcaPnAce1r-pdroigsroefsosiromn. s contributes to andro1g0e. nCoinncdluespioennsdent, TGF-β controlled cell growth. All these findings suggest PMEPA1 gene utilize the specific isoforms in order to navigate and drive cancer progression
In addition to AR and TGF-β signaling, it is worthwhile to explore the connection between PMEPA1 isoforms and other major pro-oncogenic signaling/molecules in both prostate and other solid tumors, which would further extend our knowledge to genetic defects during tumorigenesis
Summary
Prostate transmembrane protein androgen induced 1 (PMEPA1) is classified as a type 1b transmembrane protein with luminal, membrane spanning and cytoplasmic domains [1]. The predicted amino acid sequences of PMEPA1 protein from diverse species showed that the gene is highly conserved in evolution. Despite the high conservation of amino acids noted between PMEPA1 isoforms, various gene polymorphisms at individual residue level have been documented [23]. The amino acid sequence changes at these residues are mainly of non-conservative nature and involve residues 3, 75, 128, 179, 220, and 228 [6,13] Such changes are away from regions encompassing membrane spanning domain, WW domain and PY motifs. The alignment of amino 7a5cid sequencesToRfPP→MAERPGA1 from human, mouse, xenopus, chicken, and zebrafish is shown variations, the high lienveFli11g27ou89fraem2i.nAo lathciodusgTGehHLqRUuPe→M→ncEAAePSSiANPd1enptirtoytBewrPiuneantssesrcfdshroeowntmeigecttedeatldia.f,lf.2ie,n0r21e0b0n0o3t[2t[hs31p]3Ne] c-ieasndshCo-wtermmiinnoarl regions including all conserved functional domains. PPMMEEPPAA11 iissooffoorrmmss eexxoonn--iinnttrroonn ssttrruuccttuurree:: GGeennoommee sscchheemmaattiicc rreepprreesseennttaattiioonn iinnddiiccaattiinngg tthhee ssttrruuccttuurreess ooff PPMMEEPPAA11iissooffoorrmmssaannddrreessppeeccttiivveeininttrroonn--eexxoonnccoorrrreessppoonnddininggtotoPPMMEEPPAA11ggenenee[1[]1.]
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