Atlas of Genetics and Cytogenetics in Oncology and Haematology

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PPP6R3 ( phosphatase 6 regulatory subunit 3) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy. [email protected]; [email protected] Published in Atlas Database: March 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/PPP6R3ID54550ch11q13.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70657/03-2019-PPP6R3ID54550ch11q13.pdf DOI: 10.4267/2042/70657

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract bladder , lung cancer, nodular fasciitis Protein phosphatase 6 regulatory subunit 3 Identity (PPP6R3) is a regulatory subunit of the PP6 holoenzyme complex involved in the turnover of Other names: Serine/threonine-protein phosphatase serine and threonine phosphorylation events during 6 regulatory subunit 3, 11 open reading mitosis. PPP6R3 shows abundant mRNA splicing frame 23 C11orf23, SAPS domain family member 3, variants and numerous functional protein isoforms. SAPS3, SAPLa, SAPL, SAP190, sporulation- PPP6R3 is often involved in abnormal induced transcript 4-associated protein, chromosomal translocations and it is found as a DKFZp781E2374, DKFZp781O2362, fusion gene partner in different kind of . DKFZp781E17107, FLJ11058, FLJ43065, KIAA1558, MGC125711, MGC125712 Keywords PPP6R3, protein phosphatase 6 regulatory subunit 3, HGNC (Hugo): PPP6R3 C11orf23, SAPS, phosphorylation, breast cancer, Location: 11q13.2

Figure. 1. PPP6R3 gene and splicing variants/isoforms. The figure shows the locus on of the PPP6R3 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)

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related protein 5) gene. Around the genomic locus of DNA/RNA PPP6R3 take place different promoter or enhancer transcriptional elements that are located at +0.5 kb, Description +837.9 kb and -359.7 kb. PPP6R3, alias protein phosphatase 6 regulatory subunit 3, is a protein coding gene that starts at Transcription 68,460,718 nt and ends at 68,615,334 nt from qter Exists a high number of spliced version of PPP6R3 (RefSeq NC_000011.10) and with a length of (Stefansson and Brautigan, 2006) and their main 154617 bp. It is proximal to LRP5 (LDL receptor characteristics are reported in Table.1 Leng Leng MW Varia Exon Isofor Name RefSeq (1) Transcript ID Type ht Alias RefSeq (2) ht (kDa pI nt s m (bp) (aa) ) PPP6R3-201 ENST0000026563 protein Isofor 88.9 4.4 (PPP6R3- Var.5 NM_018312 23 4992 - NP_060782 793 6.9 coding m 5 5 9 003) PPP6R3- ENST0000026563 202 (PPP6R Var.44 NR_147968.1 22 ncRNA 5124 ------7.8 3-021) NM_0011641 Isofor NP_0011576 97.6 4.5 Var.6 5127 - 873 61 m 6 33 7 0 NM_0013523 Isofor NP_0013392 86.8 4.5 Var.21 4873 - 782 61 protein m 18 90 8 2 NM_0013523 coding Isofor NP_0013392 97.6 4.5 Var.28 5211 - 873 68 m 6 97 7 0 PPP6R3-203 Var. NM_0013523 ENST0000039380 Isofor NP_0013393 97.6 4.5 (PPP6R3- 24 5233 - 873 35 75 0.6 m 6 04 7 0 001) Var.41 NR_147965 4942 ------Var.43 NR_147967 5401 ------Var.45 NR_147969 ncRNA 5235 ------Var.46 NR_147970 4978 ------Var.47 NR_147971 5362 ------A, NM_0011641 Isofor NP_0011576 98.4 4.5 Var.4 5145 C11orf23 879 60 m 4 32 9 4 a, SAPLa NM_0013523 Isofor NP_0013392 73.1 4.4 Var.7 5052 - 664 47 m 7 76 5 4 NM_0013523 Isofor NP_0013392 95.2 4.5 Var.10 5037 - 850 50 m 8 79 6 5 NM_0013523 Isofor NP_0013392 96.4 4.5 Var.12 5073 - 862 52 m 10 81 5 5 NM_0013523 Isofor NP_0013392 79.5 4.4 Var.13 4704 - 717 53 m 11 82 3 9 NM_0013523 Isofor NP_0013392 99.4 4.5 Var.14 5281 - 889 54 m 12 83 7 3 PPP6R3- NM_0013523 ENST0000039380 protein Isofor NP_0013392 99.4 4.5 204 (PPP6R Var.16 25 5154 - 889 56 1.7 coding m 12 85 7 3 3-005) NM_0013523 Isofor NP_0013392 96.2 4.5 Var.20 5194 - 860 60 m 17 89 5 4 A, NM_0013523 Isofor NP_0013392 98.4 4.5 Var.24 5251 C11orf23 879 64 m 4 93 9 4 a, SAPLa NM_0013523 Isofor NP_0013392 72.1 4.4 Var.29 5149 - 654 69 m 20 98 6 5 NM_0013523 Isofor NP_0013392 87.6 4.5 Var.30 4891 - 788 70 m 21 99 9 6 NM_0013523 Isofor NP_0013393 96.4 4.5 Var.31 5200 - 862 71 m 10 00 5 5 NM_0013523 Isofor NP_0013393 97.7 4.5 Var.32 5233 - 873 72 m 24 01 3 4

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NM_0013523 Isofor NP_0013393 96.2 4.5 Var.33 5067 - 860 73 m 17 02 5 4 NM_0013523 Isofor NP_0013393 84.4 4.5 Var.34 4804 - 759 74 m 22 03 7 8 NM_0013523 Isofor NP_0013393 95.2 4.5 Var.36 5164 - 850 76 m 8 05 6 5 NM_0013523 Isofor NP_0013393 97.7 4.5 Var.37 5106 - 873 77 m 24 06 3 4 NM_0013523 Isofor NP_0013393 84.4 4.5 Var.38 4931 - 759 78 m 22 07 7 8 A, NM_0013523 Isofor NP_0013393 98.4 4.5 Var.39 5390 C11orf23 879 79 m 4 08 9 4 a, SAPLa NM_0013523 Isofor NP_0013393 95.2 4.5 Var.40 5142 - 850 80 m 8 09 6 5 Var.42 NR_147966 ncRNA 5392 ------NM_0011641 Isofor NP_0011576 94.4 4.5 Var.2 5040 - 844 63 m 2 35 4 1 PPP6R3-205 NM_0013523 ENST0000052484 protein Isofor NP_0013392 83.6 4.5 (PPP6R3- Var.15 23 4786 - 753 55 5.5 coding m 13 84 5 4 026) NM_0013523 Isofor NP_0013392 94.4 4.5 Var.23 5146 - 844 63 m 2 92 4 1 NM_0011641 Isofor NP_0011576 96.9 4.5 Var.1 5109 - 867 62 m 1 34 6 1 NM_0013523 Isofor NP_0013392 96.9 4.5 Var.8 5284 - 867 48 m 1 77 6 1 NM_0013523 Isofor NP_0013392 84.8 4.5 Var.11 4822 - 765 51 m 9 80 4 4 PPP6R3- NM_0013523 ENST0000052490 protein Isofor NP_0013392 90.1 4.4 206 (PPP6R Var.18 24 4902 - 805 58 4.5 coding m 15 87 4 9 3-007) NM_0013523 Isofor NP_0013392 87.1 4.5 Var.19 4885 - 786 59 m 16 88 5 2 NM_0013523 Isofor NP_0013392 95.6 4.5 Var.22 5129 - 856 62 m 19 91 3 2 NM_0013523 Isofor NP_0013392 95.6 4.5 Var.25 5055 - 856 65 m 19 94 3 2 ENST0000052505 retained PPP6R3-207 - - 4 513 ------0.5 intron ENST0000052515 retained PPP6R3-208 - - 2 582 ------2.1 intron ENST0000052542 nonsens PPP6R3-209 - - 8 830 ------1.5 e md ENST0000052630 retained PPP6R3-210 - - 10 4134 ------7.5 intron ENST0000052657 retained PPP6R3-211 - - 4 489 ------4.1 intron ENST0000052659 nonsens PPP6R3-212 - - 5 570 ------3.1 e md ENST0000052706 retained PPP6R3-213 - - 4 573 ------9.5 intron PPP6R3- NM_0013523 ENST0000052740 protein Isofor NP_0013392 94.5 4.5 214 (PPP6R Var.26 22 5019 - 844 66 3.6 coding m 23 95 5 6 3-020) PPP6R3- ENST0000052863 215 (PPP6R - - 5 (?) 538 ------5.5 3-012) ENST0000052917 retained PPP6R3-216 - - 4 500 ------2.1 intron

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PPP6R3- ENST0000052934 217 (PPP6R - - 4 (?) 603 ------4.5 3-011) PPP6R3- B, NM_0011641 ENST0000052971 protein Isofor NP_0011576 88.9 4.4 218 (PPP6R Var.3 23 3426 C11orf23 791 64 0.5 coding m 3 36 1 8 3-004) b, SAPLb PPP6R3- ENST0000052990 219 (PPP6R - - 7 (?) 826 ------7.5 3-009) processe ENST0000053042 d PPP6R3-220 - - 5 560 ------7.5 transcri pt PPP6R3-221 ENST0000053073 (PPP6R3- - - 2 (?) 576 ------4.1 025) PPP6R3- ENST0000053124 222 (PPP6R - - 5 (?) 687 ------4.1 3-013) ENST0000053143 retained PPP6R3-223 - - 2 590 ------2.1 intron PPP6R3-224 ENST0000053312 (PPP6R3- - - 4 (?) 551 ------7.5 027) PPP6R3- NM_0013523 ENST0000053419 protein Isofor NP_0013392 68.1 4.4 225 (PPP6R Var.17 16 5150 - 619 57 0.5 coding m 14 86 2 2 3-018) PPP6R3- ENST0000053453 226 (PPP6R - - 19 (?) 2968 ------4.5 3-008) Table.1 Alterative splicing variants and isoforms of PPP6R3. (reworked from http://grch37.ensembl.org; ttps://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org). ncRNA = non-coding RNA; nonsense md = nonsense mediated decay; (?) = undetermined; MW = molecular weight; pI = theoretical pI.

Pseudogene contrary, PPP6R3 protein is found at high levels in lung, bladder, spleen and pancreas (Ziembik et al., Currently, pseudogenes for PPP6R3 have not been 2017). detected in the . Localisation Protein PPP6R3 localize in various subcellular compartments: it is present mainly in the cytoplasm Description but it is also found in Golgi apparatus, nucleoplasm, PPP6R3 encodes the protein phosphatase 6 nucleus and associated with the plasma membrane regulatory subunit 3, which belongs to protein (Stefansson et al., 2008; phosphatase 6 (PP6) complex (York et al., 2014; https://www.ncbi.nlm.nih.gov). Guergnon et al., 2009) in which there are also PPP6R1, PPP6R2 and PPP6C . Function PP6 complex is a member of the PP2A subfamily of PPP6R3 is a subunit of protein phosphatase 6 (PP6), protein phosphatases and shows a Sit4-associated a trimeric holoenzyme of the family of protein domain (SAPS domain) (Stefansson and phosphoprotein phosphatases (PPPs), involved in the Brautigan, 2006). turnover of serine and threonine phosphorylation There are evidence about many functioning isoforms events during mitosis so much to be able to regulate for PPP6R3 protein (Table.1) that maintain the the cell cycle progression (Stefansson and Brautigan, SAPS main domain. 2007). PPP6R3 acts as a regulatory element in the PP6 protein complex and could function as a scaffold Expression for PP6 subunits. It was observed that a high amount PPP6R3 is ubiquitously expressed in human tissues of PPP6R3 in cell result in a great destabilization, and mRNA levels are highly expressed in heart upon depletion, of the catalytic subunit of PP6 (Ziembik et al., 2017; Stefansson and Brautigan, (Rusin et al.,2017). Moreover, PPP6R3 could have 2006) and also in immune cells and lymphoid an important role in maintaining immune self- tissues, in particular in T helper cells, cytotoxic T tolerance through the control of the nuclear factor cells and monocytes (Ziembik et al., 2017). On the

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kappaB (NF-kB) (Ziembik et al., 2017) and the TNF- α/NF-kB pathway (Bouwmeester et al., 2004).

Figure.2 PPP6R3 protein isoforms. Graphical representation of the PPP6R3 protein isoforms with highlight of the main verified post-translational modifications (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; Stefansson and Brautigan, 2006).

Pediatric musculoskeletal development. transcription/replication machinery (York et al., PPP6R3, along with other , seems to be 2014). involved in bone mineralization and myogenensis Homology during pediatric development (Medina-Gomez et al., 2017). However, the inner significance of this PPP6R3 is highly and abundant conserved in many relation, such as the impact on musculoskeletal species and its homology between the species is structure, on strength or weakness and on the reported in Table.2 predisposition to develop the related pathologies, DNA Prot needs to be clarified. Organism Species Symbol Identity Identity (%) (%) Interactions with the influenza A virus transcription/replication machinery. Human H.sapiens PPP6R3 100 100 PPP6R3 is a member of PP6 complex and some Chimpanzee P.troglodytes LOC710120 99.6 99.8 authors found that PP6 interact directly with two Macaco M.mulatta PPP6R3 95.6 96.4 subunits, i.e. PB1 and PB2, of the viral RNA- Wolf C.lupus PPP6R3 92.8 92.2 dependent RNA polymerase (RdRP) of the influenza Cattle B.taurus PPP6R3 91.8 96.0 A virus. This suggest a role of PP6 complex, and for Mouse M.musculus Ppp6r3 90.5 96.3 regulatory subunit PPP6R3, in the regulation of Rat R.norvegicus Ppp6r3 90.6 95.5 phosphorylation also in the influenza A virus Chicken G.gallus PPP6R3 82.8 91.5

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Xenopus Table.2 PPP6R3 homology (reworked from X.tropicalis Ppp6r3 75.6 80.3 tropicalis ps://www.ncbi.nlm.nih.gov/homologene) Zebrafish D.rerio Ppp6r3 71.6 79.0

Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref. 11q13. t(11;11)(q13;q13 Hu et al., C11orf80/PPP6R3 C11orf80 PPP6R3 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 2 ) 2018 11q13. Translocatio LUA CCDC132/PPP6R3 CCDC132 PPP6R3 7q21.2 t(7;11)(q21;q13) Adenocarcinoma Lung - 2 n D 11q13. t(11;11)(q13;q13 SKC Hu et al., CTTN/PPP6R3 CTTN PPP6R3 17q23.3 Fusion gene Malignant melanoma Skin 2 ) M 2018 11q13. t(11:17)(q13;q23 Translocatio CSHL1/PPP6R3 CSHL1 PPP6R3 17q23.3 (?) (?) (?) - 2 ) n 11q13. t(11;19)(q13;p13 Translocatio OVC Smebye et DPP9/PPP6R3 DPP9 PPP6R3 19p13.3 Adenocarcinoma Ovary 2 ) n A al., 2017 11q13. t(11;11)(q12;q13 Squamous cell Hammerman EEF1G/PPP6R3 EEF1G PPP6R3 11q12.3 Fusion gene Lung LUSC 2 ) carcinoma et al., 2012 11q13. Translocatio ITGB5 /PPP6R3 ITGB5 PPP6R3 3q21.2 t(3;11)(q21;q13) (?) (?) (?) - 2 n 11q13. t(11;11)(q13;q13 Yoshihara et KDM2A/PPP6R3 KDM2A PPP6R3 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 2 ) al., 2015 12q13.1 11q13. t(11;12)(q13;q13 Translocatio KRT5/PPP6R3 KRT5 PPP6R3 (?) (?) (?) - 3 2 ) n 16p13.1 11q13. t(11;16)(q13;p13 Translocatio MKL2/PPP6R3 MKL2 PPP6R3 (?) (?) (?) - 2 2 ) n Hu et al., NADSYN1/PPP6R NADSYN 11q13. t(11;11)(q13;q13 SKC PPP6R3 11q13.4 Fusion gene Malignant melanoma Skin 2018; Klijn 3 1 2 ) M et al., 2015 11q13. t(11;11)(q13;q13 Yoshihara et PC/PPP6R3 PC PPP6R3 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 2 ) al., 2015 11q13. t(11;11)(q13;q13 SKC Hu et al., PPP6R3/ACER3 PPP6R3 ACER3 11q13.2 Fusion gene Malignant melanoma Skin 5 ) M 2018 PPP6R3/ARHGAP 11p11. t(11;11)(p11;q13 Squamous cell Yoshihara et PPP6R3 ARHGAP1 11q13.2 Fusion gene Lung LUSC 1 2 ) carcinoma al., 2015 PPP6R3/ATP6V0D ATP6V0D Translocatio Soft PPP6R3 11q13.2 8q21.3 t(8;11)(q21;q13) Sarcoma SARC - 2 2 n tissue 11q22. t(11;11)(q13;q22 Squamous cell Hammerman PPP6R3/CNTN5 PPP6R3 CNTN5 11q13.2 Fusion gene Lung LUSC 1 ) carcinoma et al., 2012 11q13. t(11;11)(q13;q13 Hoff et al., PPP6R3/DPP3 PPP6R3 DPP3 11q13.2 Fusion gene Germ cell tumor, NOS Testis TGCT 2 ) 2016 11q13. t(11;11)(q13;q13 Yoshihara et PPP6R3/FADD PPP6R3 FADD 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 3 ) al., 2015 1p36.1 Translocatio SKC PPP6R3/EIF4G3 PPP6R3 EIF4G3 11q13.2 t(1;11)(p36;q13) Malignant melanoma Skin - 2 n M Acute lymphoblastic 11q14. t(11;11)(q13;q14 leukemia/lymphoblasti T- Liu et al., PPP6R3/INTS4 PPP6R3 INTS4 11q13.2 Fusion gene Blood 1 ) c lymphoma (T- ALL 2017 Lineage) Squamous cell Yoshihara et Lung LUSC 11q13. t(11;11)(q13;q13 carcinoma al., 2015 PPP6R3/LRP5 PPP6R3 LRP5 11q13.2 Fusion gene 2 ) Pancrea Adenocarcinoma PAAD - s Translocatio Squamous cell PPP6R3/MGAM PPP6R3 MGAM 11q13.2 7q34 t(7;11)(q34;q13) Lung LUSC - n carcinoma 11q13. t(11;11)(q13;q13 Yoshihara et PPP6R3/MTL5 PPP6R3 MTL5 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 3 ) al., 2015 11q13. t(11;11)(q13;q13 Yoshihara et PPP6R3/POLD3 PPP6R3 POLD3 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 4 ) al., 2015 Translocatio PPP6R3/PREPL PPP6R3 PREPL 11q13.2 2p21 t(2;11)(p21;q13) (?) (?) (?) - n 11q13. t(11;11)(q13;q13 Stomac Hu et al., PPP6R3/RHOD PPP6R3 RHOD 11q13.2 Fusion gene Adenocarcinoma STAD 2 ) h 2018 11q13. t(11;11)(q13;q13 Transitional cell Hu et al., PPP6R3/SHANK2 PPP6R3 SHANK2 11q13.2 Fusion gene Bladder BLCA 3 ) carcinoma 2018 11q13. t(11;11)(q13;q13 Yoshihara et PPP6R3/SPTBN2 PPP6R3 SPTBN2 11q13.2 Fusion gene Adenocarcinoma Breast BRCA 2 ) al., 2015

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Yoshihara et Adenocarcinoma Breast BRCA al., 2015 Soft McRobert et 17q11. t(11;17)(q13;q11 Translocatio Neuroblastoma NBL PPP6R3/SSH2 PPP6R3 SSH2 11q13.2 tissue al., 1992 2 ) n Acute lymphoblastic Schmiegelo leukemia/lymphoblasti Blood ALL w et al., c lymphoma 2012 11q13. t(11;11)(q13;q13 Pancrea Hu et al., PPP6R3/SSH3 PPP6R3 SSH3 11q13.2 Fusion gene Adenocarcinoma PAAD 2 ) s 2018 Soft Guo et al., Nodular fasciitis NF tissue 2016 Nacheva et Hairy cell leukemia Blood HCL al., 1992 17p13. t(11;17)(q13;p13 Translocatio PPP6R3/USP6 PPP6R3 USP6 11q13.2 Sawyer et 2 ) n al., 1995; Multiple myeloma Blood MM Sawyer et al., 2014 Chronic myeloid Stopera et Blood CML leukemia al., 1990 11q22. t(11;11)(q13;q22 Transitional cell Yoshihara et PPP6R3/YAP1 PPP6R3 YAP1 11q13.2 Fusion gene Bladder BLCA 1 ) carcinoma al., 2015 Cell carcinoma and 15q22.3 11q13. t(11;15)(q13;q22 Translocatio RAB11A/PPP6R3 RAB11A PPP6R3 endocervical Cervical CESC - 1 2 ) n adenocarcinoma 11q13. t(11;11)(q13;q13 Yoshihara et RNF121/PPP6R3 RNF121 PPP6R3 11q13.4 Fusion gene Adenocarcinoma Breast BRCA 2 ) al., 2015 11q13. Translocatio SH3RF1/PPP6R3 SH3RF1 PPP6R3 4q32.3 t(4;11)(q32;q13) (?) (?) (?) - 2 n 11q13. t(11;18)(q13;q21 Translocatio SMAD2/PPP6R3 SMAD2 PPP6R3 18q21.1 (?) (?) (?) - 2 ) n 11q13. Translocatio Squamous cell SSBP1/PPP6R3 SSBP1 PPP6R3 7q34 t(7;11)(q34;q13) Lung LUSC - 2 n carcinoma 11q13. t(11;14)(q13;q12 Translocatio Yoshihara et STRN3/PPP6R3 STRN3 PPP6R3 14q12 Adenocarcinoma Breast BRCA 2 ) n al., 2015 11q13. t(11;22)(q13;q12 Translocatio Liver hepatocellular TMPRSS6/PPP6R3 TMPRSS6 PPP6R3 22q12.3 Liver LIHC - 2 ) n carcinoma TNFRSF21/PPP6R TNFRSF2 11q13. Translocatio Banerji et PPP6R3 6p12.3 t(6;11)(p12;q13) Adenocarcinoma Breast BRCA 3 1 2 n al., 2012 11q13. Translocatio VPS50/PPP6R3 VPS50 PPP6R3 7q21.3 t(7;11)(q21;q13) (?) (?) (?) - 2 n

Table.3 PPP6R3 rearrangements: translocations and fusion genes (reworked from ps://www.ncbi.nlm.nih.gov/homologene; http://www.tumorfusions.org; https://cgap.nci.nih.gov/Chromosomes; http://quiver.archerdx.com). [ (?) ] unknown; [ - ] no reference

The fusion genes PPP6R3/ SHANK2 and PPP6R3/ Implicated in YAP1 have been found in transitional cell carcinoma PPP6R3 is involved in many and heterogeneous of the bladder (Hu et al., 2018; genomic translocations in different kind of tumors (Table. 3) and it has been proposed that this happens Yoshihara et al., 2015; because it possess a potent promotor activity (Guo et http://www.tumorfusions.org). al., 2016). Breast cancer Acute lymphoblastic leukemia (ALL) Hybrid/Mutated gene Hybrid/Mutated gene Many fusion genes and abnormal translocation was The fusion gene PPP6R3/ INTS4 has been found in discovered. C11orf80 /PPP6R3, KDM2A/PPP6R3, T-ALL (Liu et al., 2017), while a t(11;17)(q13;q11) PC/PPP6R3, PPP6R3/ FADD, PPP6R3/ MTL5, PPP6R3/ SSH2 was discovered in a childhood PPP6R3/ POLD3, PPP6R3/ SPTBN2, T/BCP (T/ B-cell precursor) ALL (Schmiegelow et t(11;17)(q13;q11) PPP6R3/SSH2, al., 2012). RNF121/PPP6R3, t(11;14)(q13;q12) STRN3/PPP6R3 and t(6;11)(p12;q13) Bladder cancer TNFRSF21/PPP6R3 have been found in breast Hybrid/Mutated gene adenocarcinoma (Hu et al., 2018; Yoshihara et al., 2015; http://www.tumorfusions.org)

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PPP6R3 (protein phosphatase 6 regulatory subunit 3) Cristiano L

Cervical carcinoma Nodular fasciitis (NF) occurs in subcutaneous tissue and it is generally a benign self-limiting Hybrid/Mutated gene myofibroblastic proliferation (Bernstein and Lattes, A t(11;15)(q13;q22) RAB11A/PPP6R3 has been 1982). Sometimes was found USP6 gene found in cervical carcinoma rearrangements (Erickson-Johnson et al., 2011) and (http://www.tumorfusions.org). surprendently in one case was revealed the presence

of PPP6R3/USP6 fusion gene with both genomic Gastric cancer amplification and overexpression (Guo et al., 2016) Hybrid/Mutated gene that could explain the more aggressive behavior seen The fusion gene PPP6R3/ RHOD has been found in in malignant NF case report. gastric adenocarcinoma (Hu et al., 2018; Hybrid/Mutated gene http://www.tumorfusions.org) It was described the fusion gene 5' PPP6R3 / 3' USP6 t(11;17)(q13;p13)PPP6R3/USP6 in deriving by the genomic translocation and fusion of a part of PPP6R3 gene, situated on chromosome 11, hematological malignancies. with a portion of USP6 gene, instead located on Hybrid/Mutated gene . In particular, the breakpoint reside A t(11;17)(q13;p13)PPP6R3/ USP6 has been found at the end of exon 1 of PPP6R3 (non-coding) and 155 in Hairy cell leukemia, Multiple myeloma, and bp upstream of coding sequence of USP6 gene (Guo Chronic myeloid leukemia (Sawyer et al., 2014 ; et al., 2016). Sawyer et al., 1995 ; Nacheva et al., 1992; Stopera et Oncogenesis al., 1990 http://www.tumorfusions.org) The presence of the novel PPP6R3/USP6 fusion Hepatocellular carcinoma gene was linked to the increase of malignancy of the Hybrid/Mutated gene nodular faciitis (NF). Other tumors were tested for the presence of this chimeric gene, such as A t(11;22)(q13;q12) TMPRSS6/PPP6R3 has been aggressive angiomyxoma , malignant peripheral found in hepatocellular carcinoma nerve sheath tumor, dermatofibroma/ benign fibrous (http://www.tumorfusions.org). histiocytoma and melanoma. In that cases the results Lung squamous cell carcinoma were negatives (Guo et al., 2016). Some authors Hybrid/Mutated gene detect PPP6R3/USP6 in hairy cell leukemia, In squamous cell carcinoma of the lung was multiple myeloma and chronic myeloid leukemia discovered the fusion gene EEF1G/PPP6R3 (Sawyer et al., 2014; Sawyer et al., 1995; Nacheva et (Hammerman et al., 2012). Other detected are: a al., 1992 ; Stopera et al., 1990). t(7;11)(q21;q13) CCDC132/PPP6R3, PPP6R3/ Nervous system tumors ARHGAP1 fusion gene, PPP6R3/ CNTN5 fusion Disease gene, PPP6R3/ LRP5 fusion gene, a Malignant peripheral nerve sheath tumors t(7;11)(q13;q34)PPP6R3/ MGAM and a (MPNSTs), also called neurofibrosarcomas, are a t(7;11)(q34;q13) SSBP1/PPP6R3 (Yoshihara et al., rare aggressive, metastatic, nerve-associated cancer 2015; Hammerman et al., 2012; type. It was found that in about 10% of this http://www.tumorfusions.org) malignancy there are mutations on PPP6R3 gene that In squamous cell carcinoma of the lung was found cause disrupt gene transcription (Rahrmann et al., the presence of the fusion gene 5' EEF1G- 3' PPP6R3 2013). In addition a t(8;11)(q21;q13)PPP6R3/ deriving by the genomic translocation and fusion of ATP6V0D2 is found in sarcoma a part of EEF1G gene with a portion of PPP6R3 (http://www.tumorfusions.org) and a gene, both located on chromosome 11 (Hammerman t(11;17)(q13;q11)PPP6R3/SSH2 is detected in et al., 2012). neuroblastoma (McRobert et al., 1992). Malignant melanoma Ovarian carcinoma Hybrid/Mutated gene Disease The fusion genes CTTN/PPP6R3, Ovarian malignancies, a type of gynecological NADSYN1/PPP6R3 and PPP6R3/ ACER3 have cancer, show high genomic instability and structural been found in malignant melanoma. In addition, a chromosomal aberrations which are believed to be t(1;11)( p36;q13) PPP6R3/ EIF4G3 has also been common mechanisms for both the inactivation of found (Hu et al., 2018; Klijn et al., 2015; tumour suppressor genes and the production of http://www.tumorfusions.org) fusion genes useful for cancer vitality. The precise Malignant Nodular Fasciitis roles and functions of these chimeric gene are not Disease always understood (Smebye et al., 2017). The fusion gene DPP9 /PPP6R3 play a role in tumorigenesis

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PPP6R3 (protein phosphatase 6 regulatory subunit 3) Cristiano L

and/or cancer progression through the loss-of- Effects on HIV-1 replication function of the DPP9 protein, a that Knockdown of PPP6R3 by short interfering RNAs act as a tumour suppressor and is a inducer of (siRNA) library screening inhibits HIV-1 replication apoptosis. in cultured Jurkat T-cells (Yeung et al., 2009). Hybrid/Mutated gene A fusion gene 5' DPP9 / 3' PPP6R3 deriving from the genomic translocation and fusion of a part of DPP9 References (dipeptidyl peptidase 9) gene, situated on with a portion of PPP6R3 gene, Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, located on chromosome 11 was found in a high- Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng grade serous ovarian carcinoma. S, Ardlie KG, Auclair D, Bautista-Piña V, Duke F, Francis J, The fusion occured between DPP9 exon 11 and Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, PPP6R3 exon 18. DPP9 is a serine protease that act Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher as a tumor suppressor and as a inducer of apoptosis SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga (Smebye et al., 2017). J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Abnormal protein Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo- The fusion between DPP9 and PPP6R3 leads to Miranda A, Meyerson M. Sequence analysis of mutations disruption and deregulation of expression of DPP9 and translocations across breast cancer subtypes. Nature. gene due to the introduction of a stop codon (TAG) 2012 Jun 20;486(7403):405-9 directly after the junction that leads to the production Bernstein KE, Lattes R. Nodular (pseudosarcomatous) of truncated form of DPP9 protein. fasciitis, a nonrecurrent lesion: clinicopathologic study of This protein loss some functional domains, i.e. the 134 cases. Cancer. 1982 Apr 15;49(8):1668-78 peptidase and esterase-lipase domains (Smebye et Bouwmeester T, Bauch A, Ruffner H, Angrand PO, al., 2017) and this causes its loss-of-function. Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Pancreatic cancer Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer Hybrid/Mutated gene G, Rick J, Kuster B, Superti-Furga G. A physical and The fusion genes PPP6R3/LRP5 and PPP6R3/ SSH3 functional map of the human TNF-alpha/NF-kappa B signal have been found in pancreas adenocarcinoma (Hu et transduction pathway. Nat Cell Biol. 2004 Feb;6(2):97-105 al., 2018; http://www.tumorfusions.org) . Comprehensive genomic characterization of squamous Testicular germ cell tumors cell lung cancers. Nature. 2012 Sep 27;489(7417):519-25 Erickson-Johnson MR, Chou MM, Evers BR, Roth CW, Disease Seys AR, Jin L, Ye Y, Lau AW, Wang X, Oliveira AM. Testicular germ cell tumors (TGCTs) are the most Nodular fasciitis: a novel model of transient neoplasia frequently diagnosed solid malignancies in young induced by MYH9-USP6 gene fusion. Lab Invest. 2011 males and men by 15 to 44 years old and that Oct;91(10):1427-33 includes two main subtypes: seminomas and non- Guergnon J, Derewenda U, Edelson JR, Brautigan DL. seminomas (Hoff et al., 2016; Znaor et al., 2014). Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical Some authors found a novel fusion gene 5' PPP6R3 repeats. BMC Biochem. 2009 Oct 16;10:24 - 3' DPP3 in pluripotent embryonal carcinomas (EC) Guo R, Wang X, Chou MM, Asmann Y, Wenger DE, Al- cell lines (Hoff et al., 2016). Ibraheemi A, Molavi DW, Aboulafia A, Jin L, Fritchie K, Hybrid/Mutated gene Oliveira JL, Jenkins RB, Westendorf JJ, Dong J, Oliveira The fusion gene 5' PPP6R3 / 3' DPP3 resulting by AM. PPP6R3-USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis Genes the translocation t(11;11)(q13;q13) and Cancer 2016 Aug;55(8):640-9 PPP6R3/DPP3 is a novel genomic chimeric Hoff AM, Alagaratnam S, Zhao S, Bruun J, Andrews PW, rearrangement occurs in vitro. Lothe RA, Skotheim RI. Identification of Novel Fusion However more studies are need to characterize it and Genes in Testicular Germ Cell Tumors Cancer Res 2016 to elucidate its exact role in testicular germ cell Jan 1;76(1):108-16 tumors. Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K, Abnormal protein Lang FM, Martinez-Ledesma E, Lee SH, Zheng S, Verhaak RGW. TumorFusions: an integrative resource for cancer- PPP6R3-DPP3 fusion gene encodes a protein of 198 associated transcript fusions Nucleic Acids Res 2018 Jan amino acids long (Hoff et al., 2016). The functions 4;46(D1):D1144-D1149 of this chimeric protein are unknown. Klijn C, Durinck S, Stawiski EW, Haverty PM, Jiang Z, Liu Type 1 diabetes mellitus 4 H, Degenhardt J, Mayba O, Gnad F, Liu J, Pau G, Reeder J, Cao Y, Mukhyala K, Selvaraj SK, Yu M, Zynda GJ, Brauer The IDDM4 locus has been localized to MJ, Wu TD, Gentleman RC, Manning G, Yauch RL, chromosome 11q13 and PPP6R3 gene is linked with Bourgon R, Stokoe D, Modrusan Z, Neve RM, de Sauvage type 1 diabetes mellitus 4 (Twells et al., 2001). FJ, Settleman J, Seshagiri S, Zhang Z. A comprehensive

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transcriptional portrait of human cancer cell lines Nat Schmiegelow K, Lausten Thomsen U, Baruchel A, Pacheco Biotechnol 2015 Mar;33(3):306-12 CE, Pieters R, Pombo-de-Oliveira MS, Andersen EW, Rostgaard K, Hjalgrim H, Pui CH. High concordance of Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson subtypes of childhood acute lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia Leukemia 2012 Apr;26(4):675-81 MR, McCastlain K, Edmonson M, Pounds SB, Shi L, Zhou X, Ma X, Sioson E, Li Y, Rusch M, Gupta P, Pei D, Cheng Smebye ML, Agostini A, Johannessen B, Thorsen J, C, Smith MA, Auvil JG, Gerhard DS, Relling MV, Winick NJ, Davidson B, Tropé CG, Heim S, Skotheim RI, Micci F. Carroll AJ, Heerema NA, Raetz E, Devidas M, Willman CL, Involvement of DPP9 in gene fusions in serous ovarian Harvey RC, Carroll WL, Dunsmore KP, Winter SS, Wood carcinoma BMC Cancer 2017 Sep 11;17(1):642 BL, Sorrentino BP, Downing JR, Loh ML, Hunger SP, Zhang Stefansson B, Ohama T, Daugherty AE, Brautigan DL. J, Mullighan CG. The genomic landscape of pediatric and Protein phosphatase 6 regulatory subunits composed of young adult T-lineage acute lymphoblastic leukemia Nat ankyrin repeat domains Biochemistry 2008 Feb Genet 2017 Aug;49(8):1211-1218 5;47(5):1442-51 McRobert TL, Rudduck C, Kees UR, Garson OM. Detection Stopera SA, Ray M, Riordan D, Christie N, Wickstrom D. of MYCN amplification in three neuroblastoma cell lines by Variant Philadelphia translocations in chronic myeloid non-radioactive chromosomal in situ hybridization Cancer leukemia: correlation with cancer breakpoints, fragile sites Genet Cytogenet 1992 Apr;59(2):128-34 and oncogenes Cancer Lett 1990 Dec 17;55(3):249-53 Medina-Gomez C, Kemp JP, Dimou NL, Kreiner E, Chesi A, Twells RC, Metzker ML, Brown SD, Cox R, Garey C, Zemel BS, Bønnelykke K, Boer CG, Ahluwalia TS, Bisgaard Hammond H, Hey PJ, Levy E, Nakagawa Y, Philips MS, H, Evangelou E, Heppe DHM, Bonewald LF, Gorski JP, Todd JA, Hess JF. The sequence and gene characterization Ghanbari M, Demissie S, Duque G, Maurano MT, Kiel DP, of a 400-kb candidate region for IDDM4 on chromosome Hsu YH, C J van der Eerden B, Ackert-Bicknell C, Reppe S, 11q13 Genomics 2001 Mar 15;72(3):231-42 Gautvik KM, Raastad T, Karasik D, van de Peppel J, Jaddoe VWV, Uitterlinden AG, Tobias JH, Grant SFA, Bagos PG, Yeung ML, Houzet L, Yedavalli VS, Jeang KT. A genome- Evans DM, Rivadeneira F. Bivariate genome-wide wide short hairpin RNA screening of jurkat T-cells for human association meta-analysis of pediatric musculoskeletal traits proteins contributing to productive HIV-1 replication J Biol reveals pleiotropic effects at the SREBF1/TOM1L2 locus Chem 2009 Jul 17;284(29):19463-73 Nat Commun 2017 Jul 25;8(1):121 York A, Hutchinson EC, Fodor E. Interactome analysis of Nacheva E, Fischer P, O'Connor S, Bloxham D, Hoggarth the influenza A virus transcription/replication machinery C, Marcus R. Complex chromosomal rearrangements in an identifies protein phosphatase 6 as a cellular factor required unusual variant of hairy cell leukemia Cancer Genet for efficient virus replication J Virol 2014 Nov;88(22):13284- Cytogenet 1992 Sep;62(2):186-90 99 Rahrmann EP, Watson AL, Keng VW, Choi K, Moriarity BS, Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna Beckmann DA, Wolf NK, Sarver A, Collins MH, Moertel CL, R, Kim H, Verhaak RG. The landscape and therapeutic Wallace MR, Gel B, Serra E, Ratner N, Largaespada DA. relevance of cancer-associated transcript fusions Forward genetic screen for malignant peripheral nerve Oncogene 2015 Sep 10;34(37):4845-54 sheath tumor formation identifies new genes and pathways driving tumorigenesis Nat Genet 2013 Jul;45(7):756-66 Ziembik MA, Bender TP, Larner JM, Brautigan DL. Functions of protein phosphatase-6 in NF-κB signaling and Rusin SF, Schlosser KA, Adamo ME, Kettenbach AN. in lymphocytes Biochem Soc Trans 2017 Jun Quantitative phosphoproteomics reveals new roles for the 15;45(3):693-701 protein phosphatase PP6 in mitotic cells Sci Signal 2015 Oct 13;8(398):rs12 Znaor A, Lortet-Tieulent J, Jemal A, Bray F. International variations and trends in testicular cancer incidence and Sawyer JR, Tian E, Heuck CJ, Epstein J, Johann DJ, mortality Eur Urol 2014 Jun;65(6):1095-106 Swanson CM, Lukacs JL, Johnson M, Binz R, Boast A, Sammartino G, Usmani S, Zangari M, Waheed S, van Rhee This article should be referenced as such: F, Barlogie B. Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in Cristiano L. PPP6R3 (protein phosphatase 6 regulatory cytogenetically defined high-risk disease Blood 2014 Apr subunit 3). Atlas Genet Cytogenet Oncol Haematol. 17;123(16):2504-12 2020; 24(2):69-78. Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenetic findings in 200 patients with multiple myeloma Cancer Genet Cytogenet 1995 Jul 1;82(1):41-9

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