| Naaladl2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | 2810043G22RikEG635702Gm1021N-acetylated alpha-linked acidic dipeptidase-like 2NAALADL2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | HomoloGene:45786;GeneCards:[1];OMA:- orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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N-Acetylated Alpha-Linked Acidic Dipeptidase Like 2 (NAALADL2) is a protein, encoded by the geneNAALADL2 in humans.NAALADL2 shares 25%–26% sequence identity and 45% sequence similarity with theglutamate carboxypeptidase II family which includes prostate cancer marker PSMA (FOLH1/NAALAD1).[2] The NAALADL2 gene is a giant gene spanning 1.37 Mb which is approximately 49 times larger than the average gene size of 28 kb.[2][3] Gene length is correlated with the number of transcript variants of a gene, as such,NAALADL2 undergoes extensive alternative splicing and has 12 splice variants as defined by Ensembl.[4][5]
The current function of NAALADL2 is unknown.NAALADL2 shows significant homology to N-acetylated alpha-linked acidic dipeptidase andtransferrin receptors. While sharing some homology with the M28B metallopeptidase family,NAALADL2 does not possess favoured amino acids at certain key positions that are highly conserved, and important for metallopeptidase function, which may imply it is catalytically inactive.[2]
NAALADL2 has been shown to be severed by aCornelia De Lange-associatedtranslocationbreakpoint at3q26.3.[2]
The rs17531088SNP inNAALADL2 was shown to be associated with Kawasaki disease in a largeGWAS comprising two independent cohorts totalling 893 KD cases plus population and family controls.[6]
NAALADL2 has been shown to have a role inprostate cancer.[7] NAALADL2 protein expression is associated with prostate tumour stage andgrade with mRNA expression predicting poor survival following radical prostatectomy in a small cohort.[7] Overexpression of NAALADL2 incell lines subsequently altered binding to extracellular matrix (ECM) components and enhanced the invasive capacity of prostate cancercells.[7] When NAALADL2 expression was artificially increased in cell lines, genes involved in thecell cycle,cell adhesion,epithelial to mesenchymal transition andcytoskeletal remodelling were altered.[7] These results suggest NAALADL2 may act to drive aggressive prostate cancer.[7]
Agenome-wide association study (GWAS) of 12,518 prostate cancer cases found a SNP; rs78943174, within the 3q26.31 (NAALADL2) locus associated with highGleason sum score.[8] A second study of SNPs occurring within common transcription factor binding sites identified the SNP; rs10936845 within a GATA2 motif.[9] This SNP increased the expression ofNAALADL2 expression in prostate cancer patients, with increased expression also predicting biochemical recurrence.[9]
In prostate cancer, somaticcopy-number gains inNAALADL2 are present in around 16% of patients with localised disease, increasing to 30% ofGleason grade 5 disease, and 50% of T stage 4 disease.[10] co-occurring with adjacent oncogeneTBL1XR1.[10] The frequency ofCNA gains inNAALADL2 associate with a number of clinical hallmarks of aggressive prostate cancer including Gleason grade, tumour stage, positivesurgical margins and cancer which has spread to thelymph nodes.[10] The frequency of copy-number gains in this genetic region also increase incastrate resistant andneuroendocrine prostate cancer.[10] The region surroundingNAALADL2 is rich in oncogenes.[11] Copy-number gains inNAALADL2 often co-occur with neighbouring oncogenes including:BCL6, ATR and PI3K family members.[10] Copy-number gains at the DNA level associate with mRNA expression changes in more than 450 known oncogenes, suggesting this region may be important in driving aggressive prostate cancer.[10]
A study of metastatic castrate resistant prostate cancer (mCRPC) has found the antisense strand ofNAALADL2 (NAALADL2-AS2) to be more than 2-fold higher in patients with mCRPC compared with healthy volunteers.[12] Patients with higherNAALADL2-AS2 expression had an improved response to enzalutamide compared to those with lower expression.[12]
Inbreast cancer, multicellular tumor spheroids (MTS) are3D cell cultures which acquire differentiated cell-cell junctions and a defined microenvironment, differentially expressing a number of adhesion molecules such asEPCAM,E-cadherin,integrins andsyndecans when compared to 2Dmonocultures.[13] NAALADL2 has been shown to be differentially expressed in MTS when compared to 2D cultures.[13] These results support a role of NAALADL2 in cell-cell interactions and agree with evidence in prostate cancer which find NAALADL2 affects cell-ECM interactions.[13][7]
SNP's inNAALADL2 have also been identified in cancer risk GWAS's for breast cancer and Lung cancer.[14][15]
It has been shown that the gene encodingNAALADL2 is located within afragile site, a genomic loci prone to breakage and subsequent repair.[16][17] In cancer, the fragile site located withinNAALADL2 has been recently shown to be the fifth most altered of all fragile sites.[18] Therefore, it has been suggested that the copy-number gains inNAALADL2 and gains in surrounding oncogenes such asGATA2,PIK3CB,ATR,SMC4,TBL1XR1,SOX2 andMUC4 may likely arise due to breakage and attempted genomic repair in this region.[19] Upon a break in this fragile site, through a process known as the fork stalling and template switching (FoSTeS), extra copies of the genes in the region surrounding the break may be duplicated.[19] Extra copies (copy-number gains) ofNAALADL2 and the genes which surround it have been shown to increase themRNA expression of these genes, leading to further dysregulation and activation of cancer-associated pathways involved in growth and proliferation.[10][19]
