By use of exon trapping from pools of chromosome 21-specific cosmids, Paoloni-Giacobino et al. (1997) identified a novel gene, which they termed TMPRSS2, that encodes a multimeric protein with a serine protease domain. The full-length cDNA encodes a predicted protein of 492 amino acids in which at least 4 domains were identified: (1) a serine protease domain of the S1 family that probably cleaves at arg or lys residues; (2) a scavenger receptor cysteine-rich (SRCR) domain (this type of domain is involved in the binding to other cell surface or extracellular molecules); (3) an LDL receptor class A (LDLRA) domain (this type of domain forms a binding site for calcium); and (4) a predicted transmembrane domain. Northern blot analysis detected expression of an approximately 3.8-kb TMPRSS2 transcript at highest levels in prostate and at lower levels in adult pancreas, liver, lung, colon, and small intestine. A minor, approximately 2.0-kb transcript was also observed in several tissues.

Guipponi et al. (2008) found Tmprss2 expression in mouse inner ear tissues, including the stria vascularis, the modiolus, and the organ of Corti, but not in the spiral ganglion.

By PCR amplification of genomic DNA from a panel of somatic cell hybrids with defined segments of chromosome 21 and by probing high-density filters of cosmids from a chromosome 21-specific library, as well as by PCR amplification using DNAs from a panel of chromosome 21-derived YACs, Paoloni-Giacobino et al. (1997) mapped TMPRSS2 to 21q22.3 between ERG (165080) and D21S56 in the same P1 fragment as MX1 (147150).

Haffner et al. (2010) showed that androgen signaling promotes corecruitment of androgen receptor (AR; 313700) and topoisomerase II-beta (TOP2B; 126431) to sites of TMPRSS2-ERG genomic breakpoints, triggering recombinogenic TOP2B-mediated double-strand breaks. Furthermore, androgen stimulation resulted in de novo production of TMPRSS2-ERG fusion transcripts in a process that required TOP2B and components of the double-strand break repair machinery. Finally, unlike normal prostate epithelium, prostatic intraepithelial neoplasia cells showed strong coexpression of AR and TOP2B. Haffner et al. (2010) concluded that their findings implicated androgen-induced TOP2B-mediated double-strand breaks in generating TMPRSS2-ERG rearrangements.

Hoffmann et al. (2020) showed that, like the SARS virus CoV-1, the CoV-2 virus enters cells by attachment to ACE2 (300332) receptors. Further, the viral spike protein (S) is processed (or primed) by the cellular protease TMPRSS2. The authors also showed that inhibitors of TMPRSS2 could block viral entry in cell culture, as could serum from convalescent patients.

TMPRSS2/ERG and TMPRSS2/ETV1 Fusion Genes

Using a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression, followed by RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) and sequencing, Tomlins et al. (2005) identified recurrent gene fusions of the 5-prime untranslated region of TMPRSS2 to ERG (165080) or ETV1 (600541) in prostate cancer (176807) tissues with outlier expression. By using FISH, Tomlins et al. (2005) demonstrated that 23 of 29 prostate cancer samples harbored rearrangements in ERG or ETV1. Cell line experiments suggested that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer.

The TMPRS22 and ERG genes are arranged tandemly on chromosome 21q22. The TMPRSS2/ERG fusion joins TMPRSS2 exons 1 or 2 usually to ERG exons 2, 3 or 4, which results in activation of the ERG transcription factor. This fusion separates the ERG 3-prime centromeric regions from the 5-prime telomeric ends; deletions of this region can also occur. Attard et al. (2008) performed FISH studies of the TMPRS22/ERG fusion gene in 445 prostate cancers from patients who had been managed conservatively. They identified an alteration, called 2+Edel, characterized by duplication of the TMPRS22/ERG fusion (detected as duplication of 3-prime ERG sequence) together with interstitial deletion of 5-prime ERG sequences. The alteration was found in 6.6% of cancers and was associated with very poor clinical outcome compared to cancers with normal ERG loci (25% vs 90% survival at 8 years). Cancers with 1 copy of 3-prime ERG (1Edel) did not have a worse clinical outcome. The findings were consistent with the hypothesis that overexpression of ERG that results from the fusion of 5-prime TMPRSS2 to 3-prime ERG is responsible for driving cancer progression. Attard et al. (2008) suggested that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, may allow stratification of prostate cancer into distinct survival categories.

The TMPRSS2-ERG fusion, present in approximately 50% of prostate cancers, is less common in prostatic intraepithelial neoplasia (PIN), raising questions about whether TMPRSS2-ERG contributes to disease initiation. King et al. (2009) identified the translational start site of a common TMPRSS2-ERG fusion and showed that transgenic TMPRSS2-ERG mice develop PIN, but only in the context of PI3 kinase pathway activation. TMPRSS2-ERG-positive human tumors are also enriched for PTEN (601728) loss, suggesting cooperation in prostate tumorigenesis.

Using dual-color FISH in LNCaP prostate cancer cells, which are androgen-sensitive but lack the TMPRSS2-ERG fusion gene, Mani et al. (2009) observed that stimulation with the androgen receptor (AR; 313700) ligand dihydrotestosterone (DHT) for 60 minutes induced proximity between the TMPRSS2 and ERG genomic loci. The effect was dependent upon AR, as the same proximity was not induced in an androgen-insensitive prostate cancer cell line. To determine whether the induced proximity facilitates formation of these gene fusions, Mani et al. (2009) treated LNCaP cells with DHT for 12 hours and then irradiated the cells to induce DNA double-strand breaks. TMPRSS2-ERG fusions were detected in 25% of clones treated with 3-Gy irradiation but in only 2.3% of those treated with 1-Gy. Mani et al. (2009) speculated that androgen signaling colocalizes the 5- and 3-prime gene fusion partners, thereby increasing the probability of a gene fusion when subjected to agents that cause DNA double-strand breaks.

Exclusion Studies

Because mutations in the TMPRSS3 gene (605511) cause a form of autosomal recessive hearing loss (601072), Guipponi et al. (2008) systematically investigated 16 TMPRSS genes as candidate genes for other forms of hearing loss. No mutations in the TMPRSS2 gene were identified among 165 patients with sporadic hearing loss.