{{infobox gene}} '''N-Acetylated Alpha-Linked Acidic Dipeptidase Like 2''' (NAALADL2) is a protein, encoded by the gene ''NAALADL2'' in humans. ''NAALADL2'' shares 25%–26% sequence identity and 45% sequence similarity with the [[glutamate carboxypeptidase II]] family which includes prostate cancer marker PSMA (''FOLH1''/''NAALAD1'').<ref name=":0">{{cite journal | vauthors = Tonkin ET, Smith M, Eichhorn P, Jones S, Imamwerdi B, Lindsay S, Jackson M, Wang TJ, Ireland M, Burn J, Krantz ID, Carr P, Strachan T | display-authors = 6 | title = A giant novel gene undergoing extensive alternative splicing is severed by a Cornelia de Lange-associated translocation breakpoint at 3q26.3 | journal = Human Genetics | volume = 115 | issue = 2 | pages = 139–48 | date = July 2004 | pmid = 15168106 | pmc = 4894837 | doi = 10.1007/s00439-004-1134-6 }}</ref> 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.<ref name=":0" /><ref>{{cite journal | vauthors = Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, Yandell M, Evans CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q, Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Gabor Miklos GL, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, Levine AJ, Roberts RJ, Simon M, Slayman C, Hunkapiller M, Bolanos R, Delcher A, Dew I, Fasulo D, Flanigan M, Florea L, Halpern A, Hannenhalli S, Kravitz S, Levy S, Mobarry C, Reinert K, Remington K, Abu-Threideh J, Beasley E, Biddick K, Bonazzi V, Brandon R, Cargill M, Chandramouliswaran I, Charlab R, Chaturvedi K, Deng Z, Di Francesco V, Dunn P, Eilbeck K, Evangelista C, Gabrielian AE, Gan W, Ge W, Gong F, Gu Z, Guan P, Heiman TJ, Higgins ME, Ji RR, Ke Z, Ketchum KA, Lai Z, Lei Y, Li Z, Li J, Liang Y, Lin X, Lu F, Merkulov GV, Milshina N, Moore HM, Naik AK, Narayan VA, Neelam B, Nusskern D, Rusch DB, Salzberg S, Shao W, Shue B, Sun J, Wang Z, Wang A, Wang X, Wang J, Wei M, Wides R, Xiao C, Yan C, Yao A, Ye J, Zhan M, Zhang W, Zhang H, Zhao Q, Zheng L, Zhong F, Zhong W, Zhu S, Zhao S, Gilbert D, Baumhueter S, Spier G, Carter C, Cravchik A, Woodage T, Ali F, An H, Awe A, Baldwin D, Baden H, Barnstead M, Barrow I, Beeson K, Busam D, Carver A, Center A, Cheng ML, Curry L, Danaher S, Davenport L, Desilets R, Dietz S, Dodson K, Doup L, Ferriera S, Garg N, Gluecksmann A, Hart B, Haynes J, Haynes C, Heiner C, Hladun S, Hostin D, Houck J, Howland T, Ibegwam C, Johnson J, Kalush F, Kline L, Koduru S, Love A, Mann F, May D, McCawley S, McIntosh T, McMullen I, Moy M, Moy L, Murphy B, Nelson K, Pfannkoch C, Pratts E, Puri V, Qureshi H, Reardon M, Rodriguez R, Rogers YH, Romblad D, Ruhfel B, Scott R, Sitter C, Smallwood M, Stewart E, Strong R, Suh E, Thomas R, Tint NN, Tse S, Vech C, Wang G, Wetter J, Williams S, Williams M, Windsor S, Winn-Deen E, Wolfe K, Zaveri J, Zaveri K, Abril JF, Guigó R, Campbell MJ, Sjolander KV, Karlak B, Kejariwal A, Mi H, Lazareva B, Hatton T, Narechania A, Diemer K, Muruganujan A, Guo N, Sato S, Bafna V, Istrail S, Lippert R, Schwartz R, Walenz B, Yooseph S, Allen D, Basu A, Baxendale J, Blick L, Caminha M, Carnes-Stine J, Caulk P, Chiang YH, Coyne M, Dahlke C, Mays A, Dombroski M, Donnelly M, Ely D, Esparham S, Fosler C, Gire H, Glanowski S, Glasser K, Glodek A, Gorokhov M, Graham K, Gropman B, Harris M, Heil J, Henderson S, Hoover J, Jennings D, Jordan C, Jordan J, Kasha J, Kagan L, Kraft C, Levitsky A, Lewis M, Liu X, Lopez J, Ma D, Majoros W, McDaniel J, Murphy S, Newman M, Nguyen T, Nguyen N, Nodell M, Pan S, Peck J, Peterson M, Rowe W, Sanders R, Scott J, Simpson M, Smith T, Sprague A, Stockwell T, Turner R, Venter E, Wang M, Wen M, Wu D, Wu M, Xia A, Zandieh A, Zhu X | s2cid = 85981305 | display-authors = 6 | title = The sequence of the human genome | journal = Science | volume = 291 | issue = 5507 | pages = 1304–51 | date = February 2001 | pmid = 11181995 | doi = 10.1126/science.1058040 | bibcode = 2001Sci...291.1304V | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Grishkevich V, Yanai I | title = Gene length and expression level shape genomic novelties | journal = Genome Research | volume = 24 | issue = 9 | pages = 1497–503 | date = September 2014 | pmid = 25015383 | pmc = 4158763 | doi = 10.1101/gr.169722.113 }}</ref><ref>{{cite journal | vauthors = Cunningham F, Achuthan P, Akanni W, Allen J, Amode MR, Armean IM, Bennett R, Bhai J, Billis K, Boddu S, Cummins C, Davidson C, Dodiya KJ, Gall A, Girón CG, Gil L, Grego T, Haggerty L, Haskell E, Hourlier T, Izuogu OG, Janacek SH, Juettemann T, Kay M, Laird MR, Lavidas I, Liu Z, Loveland JE, Marugán JC, Maurel T, McMahon AC, Moore B, Morales J, Mudge JM, Nuhn M, Ogeh D, Parker A, Parton A, Patricio M, Abdul Salam AI, Schmitt BM, Schuilenburg H, Sheppard D, Sparrow H, Stapleton E, Szuba M, Taylor K, Threadgold G, Thormann A, Vullo A, Walts B, Winterbottom A, Zadissa A, Chakiachvili M, Frankish A, Hunt SE, Kostadima M, Langridge N, Martin FJ, Muffato M, Perry E, Ruffier M, Staines DM, Trevanion SJ, Aken BL, Yates AD, Zerbino DR, Flicek P | display-authors = 6 | title = Ensembl 2019 | journal = Nucleic Acids Research | volume = 47 | issue = D1 | pages = D745–D751 | date = January 2019 | pmid = 30407521 | pmc = 6323964 | doi = 10.1093/nar/gky1113 }}</ref>
== Function == The current function of NAALADL2 is unknown. ''NAALADL2'' shows significant homology to N-acetylated alpha-linked acidic dipeptidase and [[transferrin receptor]]s. 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.<ref name=":0" />
== Clinical significance == ''NAALADL2'' has been shown to be severed by a [[Cornelia de Lange syndrome|Cornelia De Lange]]-associated [[Chromosomal translocation|translocation]] [[Chromosomal rearrangement|breakpoint]] at [[Chromosome 3|3q26.3]].<ref name=":0" />
The rs17531088 [[Single-nucleotide polymorphism|SNP]] in ''NAALADL2'' was shown to be associated with Kawasaki disease in a large [[Genome-wide association study|GWAS]] comprising two independent cohorts totalling 893 KD cases plus population and family controls.<ref>{{cite journal | vauthors = Burgner D, Davila S, Breunis WB, Ng SB, Li Y, Bonnard C, Ling L, Wright VJ, Thalamuthu A, Odam M, Shimizu C, Burns JC, Levin M, Kuijpers TW, Hibberd ML | display-authors = 6 | title = A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease | journal = PLOS Genetics | volume = 5 | issue = 1 | article-number = e1000319 | date = January 2009 | pmid = 19132087 | pmc = 2607021 | doi = 10.1371/journal.pgen.1000319 | doi-access = free }}</ref>
=== Cancer === NAALADL2 has been shown to have a role in [[prostate cancer]].<ref name=":1">{{cite journal | vauthors = Whitaker HC, Shiong LL, Kay JD, Grönberg H, Warren AY, Seipel A, Wiklund F, Thomas B, Wiklund P, Miller JL, Menon S, Ramos-Montoya A, Vowler SL, Massie C, Egevad L, Neal DE | s2cid = 40840044 | display-authors = 6 | title = N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 is overexpressed in cancer and promotes a pro-migratory and pro-metastatic phenotype | journal = Oncogene | volume = 33 | issue = 45 | pages = 5274–87 | date = November 2014 | pmid = 24240687 | doi = 10.1038/onc.2013.464 | doi-access = free }}</ref> NAALADL2 protein expression is associated with prostate tumour stage and [[Gleason grading system|grade]] with mRNA expression predicting poor survival following radical prostatectomy in a small cohort.<ref name=":1" /> Overexpression of NAALADL2 in [[cell lines]] subsequently altered binding to extracellular matrix (ECM) components and enhanced the invasive capacity of prostate cancer [[Cell lines|cells]].<ref name=":1" /> When NAALADL2 expression was artificially increased in cell lines, genes involved in the [[cell cycle]], [[cell adhesion]], [[epithelial to mesenchymal transition]] and [[Cytoskeleton|cytoskeletal]] remodelling were altered.<ref name=":1" /> These results suggest NAALADL2 may act to drive aggressive prostate cancer.<ref name=":1" />
A [[Genome-wide association study|genome-wide association study (GWAS)]] of 12,518 prostate cancer cases found a SNP; rs78943174, within the 3q26.31 (''NAALADL2'') locus associated with high [[Gleason grading system|Gleason sum score]].<ref>{{cite journal | vauthors = Berndt SI, Wang Z, Yeager M, Alavanja MC, Albanes D, Amundadottir L, Andriole G, Beane Freeman L, Campa D, Cancel-Tassin G, Canzian F, Cornu JN, Cussenot O, Diver WR, Gapstur SM, Grönberg H, Haiman CA, Henderson B, Hutchinson A, Hunter DJ, Key TJ, Kolb S, Koutros S, Kraft P, Le Marchand L, Lindström S, Machiela MJ, Ostrander EA, Riboli E, Schumacher F, Siddiq A, Stanford JL, Stevens VL, Travis RC, Tsilidis KK, Virtamo J, Weinstein S, Wilkund F, Xu J, Lilly Zheng S, Yu K, Wheeler W, Zhang H, Sampson J, Black A, Jacobs K, Hoover RN, Tucker M, Chanock SJ | display-authors = 6 | title = Two susceptibility loci identified for prostate cancer aggressiveness | journal = Nature Communications | volume = 6 | page = 6889 | date = May 2015 | pmid = 25939597 | pmc = 4422072 | doi = 10.1038/ncomms7889 | bibcode = 2015NatCo...6.6889. }}</ref> A second study of SNPs occurring within common transcription factor binding sites identified the SNP; rs10936845 within a GATA2 motif.<ref name=":2">{{cite journal | vauthors = Jin HJ, Jung S, DebRoy AR, Davuluri RV | title = Identification and validation of regulatory SNPs that modulate transcription factor chromatin binding and gene expression in prostate cancer | journal = Oncotarget | volume = 7 | issue = 34 | pages = 54616–54626 | date = August 2016 | pmid = 27409348 | pmc = 5338917 | doi = 10.18632/oncotarget.10520 }}</ref> This SNP increased the expression of ''NAALADL2'' expression in prostate cancer patients, with increased expression also predicting biochemical recurrence.<ref name=":2" />
In prostate cancer, somatic [[Copy-number variation|copy-number gains]] in ''NAALADL2'' are present in around 16% of patients with localised disease, increasing to 30% of [[Gleason grading system|Gleason grade]] 5 disease, and 50% of T stage 4 disease.<ref name=":4">{{cite journal | vauthors = Simpson BS, Camacho N, Luxton HJ, Pye H, Finn R, Heavey S, Pitt J, Moore CM, Whitaker HC | display-authors = 6 | title = Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype | journal = Communications Biology | volume = 3 | issue = 1 | page = 440 | date = August 2020 | pmid = 32796921 | pmc = 7429505 | doi = 10.1038/s42003-020-01175-x | s2cid = 221118233 | doi-access = free }}</ref> co-occurring with adjacent oncogene ''[[TBL1XR1]]''.<ref name=":4" /> The frequency of [[Copy-number variation|CNA]] gains in ''NAALADL2'' associate with a number of clinical hallmarks of aggressive prostate cancer including Gleason grade, tumour stage, positive [[Resection margin|surgical margins]] and cancer which has spread to the [[Lymph node metastases|lymph nodes]].<ref name=":4" /> The frequency of copy-number gains in this genetic region also increase in [[Prostate cancer|castrate resistant]] and [[Neuroendocrine tumor|neuroendocrine prostate cancer]].<ref name=":4" /> The region surrounding ''NAALADL2'' is rich in oncogenes.<ref>{{cite journal | vauthors = Fields AP, Justilien V, Murray NR | title = The chromosome 3q26 OncCassette: A multigenic driver of human cancer | journal = Advances in Biological Regulation | volume = 60 | pages = 47–63 | date = January 2016 | pmid = 26754874 | pmc = 4729592 | doi = 10.1016/j.jbior.2015.10.009 }}</ref> Copy-number gains in ''NAALADL2'' often co-occur with neighbouring oncogenes including: ''BCL6, ATR'' and PI3K family members.<ref name=":4" /> 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.<ref name=":4" />
A study of metastatic castrate resistant prostate cancer (mCRPC) has found the antisense strand of ''NAALADL2'' (NAALADL2-AS2) to be more than 2-fold higher in patients with mCRPC compared with healthy volunteers.<ref name=":5">{{cite journal | vauthors = Benoist GE, van Oort IM, Boerrigter E, Verhaegh GW, van Hooij O, Groen L, Smit F, de Mol P, Hamberg P, Dezentjé VO, Mehra N, Gerritsen W, Somford DM, van Erp NP, Schalken JA | s2cid = 218650088 | display-authors = 6 | title = Prognostic Value of Novel Liquid Biomarkers in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: A Prospective Observational Study | journal = Clinical Chemistry | volume = 66 | issue = 6 | pages = 842–851 | date = June 2020 | pmid = 32408351 | doi = 10.1093/clinchem/hvaa095 | doi-access = free | hdl = 2066/219814 | hdl-access = free }}</ref> Patients with higher ''NAALADL2-AS2'' expression had an improved response to enzalutamide compared to those with lower expression.<ref name=":5" />
In [[breast cancer]], multicellular tumor spheroids (MTS) are [[3D cell culture]]s which acquire differentiated cell-cell junctions and a defined microenvironment, differentially expressing a number of adhesion molecules such as [[Epithelial cell adhesion molecule|EPCAM]], [[CDH1 (gene)|E-cadherin]], [[integrin]]s and [[syndecan]]s when compared to 2D [[Cell culture|monocultures]].<ref name=":3">{{cite journal | vauthors = Pacheco-Marín R, Melendez-Zajgla J, Castillo-Rojas G, Mandujano-Tinoco E, Garcia-Venzor A, Uribe-Carvajal S, Cabrera-Orefice A, Gonzalez-Torres C, Gaytan-Cervantes J, Mitre-Aguilar IB, Maldonado V | display-authors = 6 | title = Transcriptome profile of the early stages of breast cancer tumoral spheroids | journal = Scientific Reports | volume = 6 | article-number = 23373 | date = March 2016 | pmid = 27021602 | pmc = 4810430 | doi = 10.1038/srep23373 | bibcode = 2016NatSR...623373P }}</ref> NAALADL2 has been shown to be differentially expressed in MTS when compared to 2D cultures.<ref name=":3" /> These results support a role of NAALADL2 in cell-cell interactions and agree with evidence in prostate cancer which find NAALADL2 affects cell-[[Extracellular matrix|ECM]] interactions.<ref name=":3" /><ref name=":1" />
SNP's in ''NAALADL2'' have also been identified in cancer risk GWAS's for breast cancer and Lung cancer.<ref>{{cite journal | vauthors = Murabito JM, Rosenberg CL, Finger D, Kreger BE, Levy D, Splansky GL, Antman K, Hwang SJ | display-authors = 6 | title = A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study | journal = BMC Medical Genetics | volume = 8 | pages = S6 | date = September 2007 | issue = Suppl 1 | pmid = 17903305 | pmc = 1995609 | doi = 10.1186/1471-2350-8-S1-S6 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lan Q, Hsiung CA, Matsuo K, Hong YC, Seow A, Wang Z, Hosgood HD, Chen K, Wang JC, Chatterjee N, Hu W, Wong MP, Zheng W, Caporaso N, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Yuenger J, Jacobs KB, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, Wu C, An SJ, Qian B, Lee VH, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Kim JH, Gao YT, Tsai YH, Jung YJ, Guo H, Hu Z, Hutchinson A, Wang WC, Klein R, Chung CC, Oh IJ, Chen KY, Berndt SI, He X, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Shu XO, Chen YM, Liu L, Kang CH, Hu L, Chen CH, Pao W, Kim YC, Yang TY, Xu J, Guan P, Tan W, Su J, Wang CL, Li H, Sihoe AD, Zhao Z, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Kohno T, Kweon SS, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Chow WH, Ji BT, Chan JK, Chu M, Li YJ, Yokota J, Li J, Chen H, Xiang YB, Yu CJ, Kunitoh H, Wu G, Jin L, Lo YL, Shiraishi K, Chen YH, Lin HC, Wu T, Wu YL, Yang PC, Zhou B, Shin MH, Fraumeni JF, Lin D, Chanock SJ, Rothman N | display-authors = 6 | title = Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia | journal = Nature Genetics | volume = 44 | issue = 12 | pages = 1330–5 | date = December 2012 | pmid = 23143601 | pmc = 4169232 | doi = 10.1038/ng.2456 }}</ref>
=== Fragile site === It has been shown that the gene encoding ''NAALADL2'' is located within a [[fragile site]], a genomic loci prone to breakage and subsequent repair.<ref>{{cite journal | vauthors = Sugio Y, Kuroki Y | title = Family study of common fragile sites | journal = Human Genetics | volume = 82 | issue = 2 | pages = 191–3 | date = May 1989 | pmid = 2722197 | doi = 10.1007/BF00284056 | s2cid = 2624650 }}</ref><ref>{{cite journal | vauthors = Murano I, Kuwano A, Kajii T | title = Fibroblast-specific common fragile sites induced by aphidicolin | journal = Human Genetics | volume = 83 | issue = 1 | pages = 45–8 | date = August 1989 | pmid = 2504659 | doi = 10.1007/BF00274145 | s2cid = 19568677 }}</ref> In cancer, the fragile site located within ''NAALADL2'' has been recently shown to be the fifth most altered of all fragile sites.<ref>{{cite journal | vauthors = Li Y, Roberts ND, Wala JA, Shapira O, Schumacher SE, Kumar K, Khurana E, Waszak S, Korbel JO, Haber JE, Imielinski M, Weischenfeldt J, Beroukhim R, Campbell PJ | display-authors = 6 | title = Patterns of somatic structural variation in human cancer genomes | journal = Nature | volume = 578 | issue = 7793 | pages = 112–121 | date = February 2020 | pmid = 32025012 | pmc = 7025897 | doi = 10.1038/s41586-019-1913-9 | bibcode = 2020Natur.578..112L }}</ref> Therefore, it has been suggested that the copy-number gains in ''NAALADL2'' and gains in surrounding oncogenes such as ''[[GATA2]], [[PIK3CB]], [[Ataxia telangiectasia and Rad3 related|ATR]], [[SMC4]], [[TBL1XR1]], [[SOX2]]'' and ''[[Mucin 4|MUC4]]'' may likely arise due to breakage and attempted genomic repair in this region.<ref name=":6">{{cite journal | vauthors = Simpson BS, Pye H, Whitaker HC | title = The oncological relevance of fragile sites in cancer | journal = Communications Biology | volume = 4 | issue = 1 | page = 567 | date = May 2021 | pmid = 33980983 | pmc = 8115686 | doi = 10.1038/s42003-021-02020-5 }}</ref> 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.<ref name=":6" /> Extra copies (copy-number gains) of ''NAALADL2'' and the genes which surround it have been shown to increase the [[Messenger RNA|mRNA expression]] of these genes, leading to further dysregulation and activation of cancer-associated pathways involved in growth and proliferation.<ref name=":4" /><ref name=":6" />
== References == {{Reflist}}
[[Category:Genes]] [[Category:Prostate cancer]] [[Category:Proteins]]