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PPP6R3 (protein phosphatase 6 regulatory subunit 3)

Written2019-03Luigi Cristiano
Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy. prestige.infomed@gmail.com; luigicristiano@libero.it

Abstract Protein phosphatase 6 regulatory subunit 3 (PPP6R3) is a regulatory subunit of the PP6 holoenzyme complex involved in the turnover of serine and threonine phosphorylation events during mitosis. PPP6R3 shows abundant mRNA splicing variants and numerous functional protein isoforms. PPP6R3 gene is often involved in abnormal chromosomal translocations and it is found as a fusion gene partner in different kind of cancers.

Keywords PPP6R3, protein phosphatase 6 regulatory subunit 3, C11orf23, SAPS, phosphorylation, breast cancer, bladder cancer, lung cancer, nodular fasciitis

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)Serine/threonine-protein phosphatase 6 regulatory subunit 3
chromosome 11 open reading frame 23 C11orf23
SAPS domain family member 3, SAPS3
SAPLa
SAPL
SAP190
sporulation-induced transcript 4-associated protein
DKFZp781E2374
DKFZp781O2362
DKFZp781E17107
FLJ11058
FLJ43065
KIAA1558
MGC125711
MGC125712
HGNC (Hugo) PPP6R3
HGNC Alias symbSAPLa
DKFZp781E2374
DKFZp781O2362
DKFZp781E17107
SAP190
SAPL
PP6R3
FLJ11058
FLJ43065
KIAA1558
MGC125711
MGC125712
HGNC Alias namesporulation-induced transcript 4-associated protein
HGNC Previous nameC11orf23
 SAPS3
HGNC Previous namechromosome 11 open reading frame 23
 SAPS domain family, member 3
 protein phosphatase 6, regulatory subunit 3
LocusID (NCBI) 55291
Atlas_Id 54550
Location 11q13.2  [Link to chromosome band 11q13]
Location_base_pair Starts at 68460752 and ends at 68615333 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PPP6R3.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Figure. 1. PPP6R3 gene and splicing variants/isoforms. The figure shows the locus on chromosome 11 of the PPP6R3 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)
Description PPP6R3, alias protein phosphatase 6 regulatory subunit 3, is a protein coding gene that starts at 68,460,718 nt and ends at 68,615,334 nt from qter (RefSeq NC_000011.10) and with a length of 154617 bp. It is proximal to LRP5 (LDL receptor related protein 5) gene. Around the genomic locus of PPP6R3 take place different promoter or enhancer transcriptional elements that are located at +0.5 kb, +837.9 kb and -359.7 kb.
Transcription Exists a high number of spliced version of PPP6R3 (Stefansson and Brautigan, 2006) and their main characteristics are reported in Table.1
Name Variant RefSeq (1) Transcript ID Exons Type Lenght (bp) Isoform Alias RefSeq (2) Lenght (aa) MW (kDa) pI
PPP6R3-201 (PPP6R3-003)Var.5 NM_018312ENST00000265636.923protein coding4992Isoform 5-NP_06078279388.954.49
PPP6R3-202  (PPP6R3-021)Var.44NR_147968.1ENST00000265637.822ncRNA5124------
PPP6R3-203 (PPP6R3-001)Var.6NM_001164161ENST00000393800.624protein coding5127Isoform 6-NP_00115763387397.674.50
Var.21NM_0013523614873Isoform 18-NP_00133929078286.884.52
Var.28NM_0013523685211Isoform 6-NP_00133929787397.674.50
Var. 35NM_0013523755233Isoform 6-NP_00133930487397.674.50
Var.41NR_147965ncRNA4942------
Var.43NR_1479675401------
Var.45NR_147969 5235------
Var.46NR_147970 4978------
Var.47NR_1479715362------
PPP6R3-204 (PPP6R3-005)Var.4NM_001164160 ENST00000393801.725protein coding5145Isoform 4A, C11orf23a, SAPLaNP_001157632 87998.494.54
Var.7NM_001352347 5052Isoform 7-NP_001339276 66473.154.44
Var.10NM_001352350 5037Isoform 8-NP_001339279 85095.264.55
Var.12NM_001352352 5073Isoform 10-NP_001339281 86296.454.55
Var.13NM_001352353 4704Isoform 11-NP_001339282 71779.534.49
Var.14NM_001352354 5281Isoform 12-NP_001339283 88999.474.53
Var.16NM_001352356 5154Isoform 12-NP_001339285 88999.474.53
Var.20NM_001352360 5194Isoform 17-NP_001339289 86096.254.54
Var.24NM_001352364 5251Isoform 4A, C11orf23a, SAPLaNP_001339293 87998.494.54
Var.29NM_001352369 5149Isoform 20-NP_001339298 65472.164.45
Var.30NM_001352370 4891Isoform 21-NP_001339299 78887.694.56
Var.31NM_001352371 5200Isoform 10-NP_001339300 86296.454.55
Var.32NM_001352372 5233Isoform 24-NP_001339301 87397.734.54
Var.33NM_001352373 5067Isoform 17-NP_001339302 86096.254.54
Var.34NM_001352374 4804Isoform 22-NP_001339303 75984.474.58
Var.36NM_001352376 5164Isoform 8-NP_001339305 85095.264.55
Var.37NM_001352377 5106Isoform 24-NP_001339306 87397.734.54
Var.38NM_001352378 4931Isoform 22-NP_001339307 75984.474.58
Var.39NM_001352379 5390Isoform 4A, C11orf23a, SAPLaNP_001339308 87998.494.54
Var.40NM_001352380 5142Isoform 8-NP_001339309 85095.264.55
Var.42NR_147966ncRNA5392------
PPP6R3-205 (PPP6R3-026)Var.2NM_001164163 ENST00000524845.5 23protein coding5040Isoform 2-NP_001157635 84494.444.51
Var.15NM_001352355 4786Isoform 13-NP_001339284 75383.654.54
Var.23NM_0013523635146Isoform 2-NP_00133929284494.444.51
PPP6R3-206  (PPP6R3-007)Var.1NM_001164162 ENST00000524904.524protein coding5109Isoform 1-NP_001157634 86796.964.51
Var.8NM_001352348 5284Isoform 1-NP_001339277 86796.964.51
Var.11NM_001352351 4822Isoform 9-NP_001339280 76584.844.54
Var.18NM_001352358 4902Isoform 15-NP_001339287 80590.144.49
Var.19NM_001352359 4885Isoform 16-NP_001339288 78687.154.52
Var.22NM_001352362 5129Isoform 19-NP_001339291 85695.634.52
Var.25NM_0013523655055Isoform 19-NP_00133929485695.634.52
PPP6R3-207--ENST00000525050.5 4retained intron513------
PPP6R3-208--ENST00000525152.12retained intron582------
PPP6R3-209--ENST00000525421.5 8nonsense md830------
PPP6R3-210--ENST00000526307.510retained intron4134------
PPP6R3-211--ENST00000526574.1 4retained intron489------
PPP6R3-212--ENST00000526593.15nonsense md570------
PPP6R3-213--ENST00000527069.5 4retained intron573------
PPP6R3-214  (PPP6R3-020)Var.26NM_001352366ENST00000527403.622protein coding5019Isoform 23-NP_00133929584494.554.56
PPP6R3-215  (PPP6R3-012)--ENST00000528635.55(?)538------
PPP6R3-216--ENST00000529172.1 4retained intron500------
PPP6R3-217  (PPP6R3-011)--ENST00000529344.5 4(?)603------
PPP6R3-218  (PPP6R3-004)Var.3NM_001164164ENST00000529710.5 23protein coding3426Isoform 3B, C11orf23b, SAPLbNP_00115763679188.914.48
PPP6R3-219  (PPP6R3-009)--ENST00000529907.5 7(?)826------
PPP6R3-220--ENST00000530427.55processed transcript560------
PPP6R3-221 (PPP6R3-025)--ENST00000530734.1 2(?)576------
PPP6R3-222  (PPP6R3-013)--ENST00000531244.1 5(?)687------
PPP6R3-223--ENST00000531432.12retained intron590------
PPP6R3-224 (PPP6R3-027)--ENST00000533127.5 4(?)551------
PPP6R3-225  (PPP6R3-018)Var.17NM_001352357ENST00000534190.5 16protein coding5150Isoform 14-NP_00133928661968.124.42
PPP6R3-226  (PPP6R3-008)--ENST00000534534.5 19(?)2968------

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 Currently, pseudogenes for PPP6R3 have not been detected in the human genome.

Protein

 
  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).
Description PPP6R3 encodes the protein phosphatase 6 regulatory subunit 3, which belongs to protein phosphatase 6 (PP6) complex (York et al., 2014; Guergnon et al., 2009) in which there are also PPP6R1, PPP6R2 and PPP6C proteins. PP6 complex is a member of the PP2A subfamily of protein phosphatases and shows a Sit4-associated protein domain (SAPS domain) (Stefansson and Brautigan, 2006). There are evidence about many functioning isoforms for PPP6R3 protein (Table.1) that maintain the SAPS main domain.
Expression PPP6R3 is ubiquitously expressed in human tissues and mRNA levels are highly expressed in heart (Ziembik et al., 2017; Stefansson and Brautigan, 2006) and also in immune cells and lymphoid tissues, in particular in T helper cells, cytotoxic T cells and monocytes (Ziembik et al., 2017). On the contrary, PPP6R3 protein is found at high levels in lung, bladder, spleen and pancreas (Ziembik et al., 2017).
Localisation PPP6R3 localize in various subcellular compartments: it is present mainly in the cytoplasm but it is also found in Golgi apparatus, nucleoplasm, nucleus and associated with the plasma membrane (Stefansson et al., 2008; https://www.ncbi.nlm.nih.gov).
Function PPP6R3 is a subunit of protein phosphatase 6 (PP6), a trimeric holoenzyme of the family of phosphoprotein phosphatases (PPPs), involved in the turnover of serine and threonine phosphorylation events during mitosis so much to be able to regulate the cell cycle progression (Stefansson and Brautigan, 2007). PPP6R3 acts as a regulatory element in the PP6 protein complex and could function as a scaffold for PP6 subunits. It was observed that a high amount of PPP6R3 in cell result in a great destabilization, upon depletion, of the catalytic subunit of PP6 (Rusin et al.,2017). Moreover, PPP6R3 could have an important role in maintaining immune self-tolerance through the control of the nuclear factor kappaB (NF-kB) (Ziembik et al., 2017) and the TNF- α/NF-kB pathway (Bouwmeester et al., 2004).
Pediatric musculoskeletal development. PPP6R3, along with other genes, seems to be involved in bone mineralization and myogenensis during pediatric development (Medina-Gomez et al., 2017). However, the inner significance of this relation, such as the impact on musculoskeletal structure, on strength or weakness and on the predisposition to develop the related pathologies, needs to be clarified.
Interactions with the influenza A virus transcription/replication machinery. PPP6R3 is a member of PP6 complex and some authors found that PP6 interact directly with two subunits, i.e. PB1 and PB2, of the viral RNA-dependent RNA polymerase (RdRP) of the influenza A virus. This suggest a role of PP6 complex, and for regulatory subunit PPP6R3, in the regulation of phosphorylation also in the influenza A virus transcription/replication machinery (York et al., 2014).
Homology PPP6R3 is highly and abundant conserved in many species and its homology between the species is reported in Table.2
OrganismSpeciesSymbol DNA Identity (%)Prot Identity (%)
HumanH.sapiensPPP6R3100100
ChimpanzeeP.troglodytesLOC71012099.699.8
MacacoM.mulattaPPP6R395.696.4
WolfC.lupusPPP6R392.892.2
CattleB.taurusPPP6R391.896.0
Mouse M.musculus Ppp6r390.596.3
RatR.norvegicus Ppp6r390.695.5
ChickenG.gallusPPP6R382.891.5
Xenopus tropicalisX.tropicalis Ppp6r375.680.3
Zebrafish D.rerio Ppp6r371.679.0

Table.2 PPP6R3 homology (reworked from ps://www.ncbi.nlm.nih.gov/homologene)

Implicated in

Note PPP6R3 is involved in many and heterogeneous genomic translocations in different kind of tumors (Table. 3) and it has been proposed that this happens because it possess a potent promotor activity (Guo et al., 2016).
Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref.
C11orf80/PPP6R3C11orf80PPP6R3 11q13.211q13.2 t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAHu et al., 2018
CCDC132/PPP6R3 CCDC132PPP6R3 7q21.2 11q13.2t(7;11)(q21;q13)TranslocationAdenocarcinomaLungLUAD-
CTTN/PPP6R3CTTNPPP6R317q23.311q13.2t(11;11)(q13;q13)Fusion geneMalignant melanomaSkinSKCMHu et al., 2018
CSHL1/PPP6R3CSHL1PPP6R3 17q23.311q13.2t(11:17)(q13;q23)Translocation(?)(?)(?)-
DPP9/PPP6R3DPP9PPP6R3 19p13.311q13.2t(11;19)(q13;p13) TranslocationAdenocarcinomaOvaryOVCASmebye et al., 2017
EEF1G/PPP6R3 EEF1GPPP6R311q12.311q13.2t(11;11)(q12;q13)Fusion geneSquamous cell carcinomaLungLUSCHammerman et al., 2012
ITGB5 /PPP6R3ITGB5 PPP6R33q21.211q13.2t(3;11)(q21;q13)Translocation(?)(?)(?)-
KDM2A/PPP6R3 KDM2APPP6R311q13.211q13.2t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
KRT5/PPP6R3KRT5PPP6R312q13.1311q13.2t(11;12)(q13;q13)Translocation(?)(?)(?)-
MKL2/PPP6R3MKL2 PPP6R316p13.1211q13.2t(11;16)(q13;p13)Translocation(?)(?)(?)-
NADSYN1/PPP6R3NADSYN1PPP6R3 11q13.411q13.2t(11;11)(q13;q13)Fusion geneMalignant melanomaSkinSKCMHu et al., 2018; Klijn et al., 2015
PC/PPP6R3PCPPP6R311q13.211q13.2t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
PPP6R3/ACER3PPP6R3ACER311q13.2 11q13.5t(11;11)(q13;q13)Fusion geneMalignant melanomaSkinSKCMHu et al., 2018
PPP6R3/ARHGAP1PPP6R3ARHGAP111q13.211p11.2t(11;11)(p11;q13)Fusion geneSquamous cell carcinomaLungLUSCYoshihara et al., 2015
PPP6R3/ATP6V0D2PPP6R3ATP6V0D211q13.2 8q21.3t(8;11)(q21;q13)TranslocationSarcomaSoft tissueSARC-
PPP6R3/CNTN5PPP6R3CNTN511q13.211q22.1t(11;11)(q13;q22)Fusion geneSquamous cell carcinomaLungLUSCHammerman et al., 2012
PPP6R3/DPP3PPP6R3DPP311q13.211q13.2 t(11;11)(q13;q13)Fusion geneGerm cell tumor, NOSTestisTGCTHoff et al., 2016
PPP6R3/FADD PPP6R3FADD 11q13.211q13.3 t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
PPP6R3/EIF4G3PPP6R3EIF4G311q13.2 1p36.12t(1;11)(p36;q13)TranslocationMalignant melanomaSkinSKCM-
PPP6R3/INTS4 PPP6R3INTS4 11q13.2 11q14.1t(11;11)(q13;q14) Fusion geneAcute lymphoblastic leukemia/lymphoblastic lymphoma (T-Lineage)BloodT-ALLLiu et al., 2017
PPP6R3/LRP5PPP6R3LRP511q13.211q13.2 t(11;11)(q13;q13)Fusion geneSquamous cell carcinomaLungLUSCYoshihara et al., 2015
AdenocarcinomaPancreasPAAD-
PPP6R3/MGAMPPP6R3MGAM11q13.2 7q34t(7;11)(q34;q13)TranslocationSquamous cell carcinomaLungLUSC-
PPP6R3/MTL5PPP6R3MTL511q13.211q13.3 t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
PPP6R3/POLD3PPP6R3POLD311q13.211q13.4t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
PPP6R3/PREPLPPP6R3PREPL11q13.22p21t(2;11)(p21;q13)Translocation(?)(?)(?)-
 PPP6R3/RHODPPP6R3RHOD11q13.2 11q13.2 t(11;11)(q13;q13)Fusion geneAdenocarcinomaStomachSTADHu et al., 2018
PPP6R3/SHANK2PPP6R3SHANK211q13.2 11q13.3 t(11;11)(q13;q13)Fusion gene Transitional cell carcinomaBladderBLCAHu et al., 2018
PPP6R3/SPTBN2PPP6R3SPTBN211q13.211q13.2t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
PPP6R3/SSH2PPP6R3SSH211q13.217q11.2t(11;17)(q13;q11)TranslocationAdenocarcinomaBreastBRCAYoshihara et al., 2015
NeuroblastomaSoft tissueNBLMcRobert et al., 1992
Acute lymphoblastic leukemia/lymphoblastic lymphomaBloodALLSchmiegelow et al., 2012
PPP6R3/SSH3PPP6R3SSH311q13.2 11q13.2  t(11;11)(q13;q13)Fusion geneAdenocarcinomaPancreasPAADHu et al., 2018
PPP6R3/USP6 PPP6R3USP6 11q13.2 17p13.2 t(11;17)(q13;p13) TranslocationNodular fasciitisSoft tissueNFGuo et al., 2016
Hairy cell leukemiaBloodHCLNacheva et al., 1992
Multiple myelomaBloodMMSawyer et al., 1995; Sawyer et al., 2014
 Chronic myeloid leukemiaBloodCMLStopera et al., 1990
PPP6R3/YAP1PPP6R3YAP111q13.211q22.1 t(11;11)(q13;q22)Fusion gene Transitional cell carcinomaBladderBLCAYoshihara et al., 2015
RAB11A/PPP6R3RAB11APPP6R3 15q22.31 11q13.2t(11;15)(q13;q22)TranslocationCell carcinoma and endocervical adenocarcinomaCervicalCESC-
RNF121/PPP6R3 RNF121PPP6R311q13.411q13.2t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015
SH3RF1/PPP6R3SH3RF1PPP6R34q32.311q13.2t(4;11)(q32;q13)Translocation(?)(?)(?)-
SMAD2/PPP6R3SMAD2PPP6R318q21.111q13.2t(11;18)(q13;q21)Translocation(?)(?)(?)-
SSBP1/PPP6R3SSBP1PPP6R3 7q3411q13.2t(7;11)(q34;q13)TranslocationSquamous cell carcinomaLungLUSC-
STRN3/PPP6R3 STRN3PPP6R314q1211q13.2 t(11;14)(q13;q12)TranslocationAdenocarcinomaBreastBRCAYoshihara et al., 2015
TMPRSS6/PPP6R3TMPRSS6PPP6R3 22q12.311q13.2t(11;22)(q13;q12)TranslocationLiver hepatocellular carcinomaLiver LIHC-
TNFRSF21/PPP6R3TNFRSF21PPP6R3 6p12.3 11q13.2t(6;11)(p12;q13)TranslocationAdenocarcinomaBreastBRCABanerji et al., 2012
VPS50/PPP6R3VPS50PPP6R37q21.311q13.2t(7;11)(q21;q13)Translocation(?)(?)(?)-

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
  
Entity Acute lymphoblastic leukemia (ALL)
Hybrid/Mutated Gene The fusion gene PPP6R3/ INTS4 has been found in T-ALL (Liu et al., 2017), while a t(11;17)(q13;q11) PPP6R3/ SSH2 was discovered in a childhood T/BCP (T/ B-cell precursor) ALL (Schmiegelow et al., 2012).
  
  
Entity Bladder cancer
Hybrid/Mutated Gene The fusion genes PPP6R3/ SHANK2 and PPP6R3/ YAP1 have been found in transitional cell carcinoma of the bladder (Hu et al., 2018; Yoshihara et al., 2015; http://www.tumorfusions.org).
  
  
Entity Breast cancer
Hybrid/Mutated Gene Many fusion genes and abnormal translocation was discovered. C11orf80 /PPP6R3, KDM2A/PPP6R3, PC/PPP6R3, PPP6R3/ FADD, PPP6R3/ MTL5, PPP6R3/ POLD3, PPP6R3/ SPTBN2, t(11;17)(q13;q11) PPP6R3/SSH2, RNF121/PPP6R3, t(11;14)(q13;q12) STRN3/PPP6R3 and t(6;11)(p12;q13) TNFRSF21/PPP6R3 have been found in breast adenocarcinoma (Hu et al., 2018; Yoshihara et al., 2015; http://www.tumorfusions.org)
  
  
Entity Cervical carcinoma
Hybrid/Mutated Gene A t(11;15)(q13;q22) RAB11A/PPP6R3 has been found in cervical carcinoma (http://www.tumorfusions.org).
  
  
Entity Gastric cancer
Hybrid/Mutated Gene The fusion gene PPP6R3/ RHOD has been found in gastric adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)
  
  
Entity t(11;17)(q13;p13)PPP6R3/USP6 in hematological malignancies.
Hybrid/Mutated Gene A t(11;17)(q13;p13)PPP6R3/ USP6 has been found in Hairy cell leukemia, Multiple myeloma, and Chronic myeloid leukemia (Sawyer et al., 2014 ; Sawyer et al., 1995 ; Nacheva et al., 1992; Stopera et al., 1990 http://www.tumorfusions.org)
  
  
Entity Hepatocellular carcinoma
Hybrid/Mutated Gene A t(11;22)(q13;q12) TMPRSS6/PPP6R3 has been found in hepatocellular carcinoma (http://www.tumorfusions.org).
  
  
Entity Lung squamous cell carcinoma
Hybrid/Mutated Gene In squamous cell carcinoma of the lung was discovered the fusion gene EEF1G/PPP6R3 (Hammerman et al., 2012). Other detected are: a t(7;11)(q21;q13) CCDC132/PPP6R3, PPP6R3/ ARHGAP1 fusion gene, PPP6R3/ CNTN5 fusion gene, PPP6R3/ LRP5 fusion gene, a t(7;11)(q13;q34)PPP6R3/ MGAM and a t(7;11)(q34;q13) SSBP1/PPP6R3 (Yoshihara et al., 2015; Hammerman et al., 2012; http://www.tumorfusions.org)
In squamous cell carcinoma of the lung was found the presence of the fusion gene 5' EEF1G- 3' PPP6R3 deriving by the genomic translocation and fusion of a part of EEF1G gene with a portion of PPP6R3 gene, both located on chromosome 11 (Hammerman et al., 2012).
  
  
Entity Malignant melanoma
Hybrid/Mutated Gene The fusion genes CTTN/PPP6R3, NADSYN1/PPP6R3 and PPP6R3/ ACER3 have been found in malignant melanoma. In addition, a t(1;11)( p36;q13) PPP6R3/ EIF4G3 has also been found (Hu et al., 2018; Klijn et al., 2015; http://www.tumorfusions.org)
  
  
Entity Malignant Nodular Fasciitis
Disease Nodular fasciitis (NF) occurs in subcutaneous tissue and it is generally a benign self-limiting myofibroblastic proliferation (Bernstein and Lattes, 1982). Sometimes was found USP6 gene rearrangements (Erickson-Johnson et al., 2011) and surprendently in one case was revealed the presence of PPP6R3/USP6 fusion gene with both genomic amplification and overexpression (Guo et al., 2016) that could explain the more aggressive behavior seen in malignant NF case report.
Hybrid/Mutated Gene It was described the fusion gene 5' PPP6R3 / 3' USP6 deriving by the genomic translocation and fusion of a part of PPP6R3 gene, situated on chromosome 11, with a portion of USP6 gene, instead located on chromosome 17. In particular, the breakpoint reside at the end of exon 1 of PPP6R3 (non-coding) and 155 bp upstream of coding sequence of USP6 gene (Guo et al., 2016).
Oncogenesis The presence of the novel PPP6R3/USP6 fusion gene was linked to the increase of malignancy of the nodular faciitis (NF). Other tumors were tested for the presence of this chimeric gene, such as aggressive angiomyxoma , malignant peripheral nerve sheath tumor, dermatofibroma/ benign fibrous histiocytoma and melanoma. In that cases the results were negatives (Guo et al., 2016). Some authors detect PPP6R3/USP6 in hairy cell leukemia, multiple myeloma and chronic myeloid leukemia (Sawyer et al., 2014; Sawyer et al., 1995; Nacheva et al., 1992 ; Stopera et al., 1990).
  
  
Entity Nervous system tumors
Disease Malignant peripheral nerve sheath tumors (MPNSTs), also called neurofibrosarcomas, are a rare aggressive, metastatic, nerve-associated cancer type. It was found that in about 10% of this malignancy there are mutations on PPP6R3 gene that cause disrupt gene transcription (Rahrmann et al., 2013). In addition a t(8;11)(q21;q13)PPP6R3/ ATP6V0D2 is found in sarcoma (http://www.tumorfusions.org) and a t(11;17)(q13;q11)PPP6R3/SSH2 is detected in neuroblastoma (McRobert et al., 1992).
  
  
Entity Ovarian carcinoma
Disease Ovarian malignancies, a type of gynecological cancer, show high genomic instability and structural chromosomal aberrations which are believed to be common mechanisms for both the inactivation of tumour suppressor genes and the production of fusion genes useful for cancer vitality. The precise roles and functions of these chimeric gene are not always understood (Smebye et al., 2017). The fusion gene DPP9 /PPP6R3 play a role in tumorigenesis and/or cancer progression through the loss-of-function of the DPP9 protein, a serine protease that act as a tumour suppressor and is a inducer of apoptosis.
Hybrid/Mutated Gene A fusion gene 5' DPP9 / 3' PPP6R3 deriving from the genomic translocation and fusion of a part of DPP9 (dipeptidyl peptidase 9) gene, situated on chromosome 19 with a portion of PPP6R3 gene, located on chromosome 11 was found in a high-grade serous ovarian carcinoma. The fusion occured between DPP9 exon 11 and PPP6R3 exon 18. DPP9 is a serine protease that act as a tumor suppressor and as a inducer of apoptosis (Smebye et al., 2017).
Abnormal Protein The fusion between DPP9 and PPP6R3 leads to disruption and deregulation of expression of DPP9 gene due to the introduction of a stop codon (TAG) directly after the junction that leads to the production of truncated form of DPP9 protein. This protein loss some functional domains, i.e. the peptidase and esterase-lipase domains (Smebye et al., 2017) and this causes its loss-of-function.
  
  
Entity Pancreatic cancer
Hybrid/Mutated Gene The fusion genes PPP6R3/LRP5 and PPP6R3/ SSH3 have been found in pancreas adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)
  
  
Entity Testicular germ cell tumors
Disease Testicular germ cell tumors (TGCTs) are the most frequently diagnosed solid malignancies in young males and men by 15 to 44 years old and that includes two main subtypes: seminomas and non-seminomas (Hoff et al., 2016; Znaor et al., 2014). Some authors found a novel fusion gene 5' PPP6R3 - 3' DPP3 in pluripotent embryonal carcinomas (EC) cell lines (Hoff et al., 2016).
Hybrid/Mutated Gene The fusion gene 5' PPP6R3 / 3' DPP3 resulting by the translocation t(11;11)(q13;q13) and PPP6R3/DPP3 is a novel genomic chimeric rearrangement occurs in vitro. However more studies are need to characterize it and to elucidate its exact role in testicular germ cell tumors.
Abnormal Protein PPP6R3-DPP3 fusion gene encodes a protein of 198 amino acids long (Hoff et al., 2016). The functions of this chimeric protein are unknown.
  
  
Entity Type 1 diabetes mellitus 4
Note The IDDM4 locus has been localized to chromosome 11q13 and PPP6R3 gene is linked with type 1 diabetes mellitus 4 (Twells et al., 2001).
  
  
Entity Effects on HIV-1 replication
Note Knockdown of PPP6R3 by short interfering RNAs (siRNA) library screening inhibits HIV-1 replication in cultured Jurkat T-cells (Yeung et al., 2009).
  

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Citation

This paper should be referenced as such :
Luigi Cristiano
PPP6R3 (protein phosphatase 6 regulatory subunit 3)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(2):69-78.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(11;11)(q13;q14) PPP6R3::INTS4

External links

Nomenclature
HGNC (Hugo)PPP6R3   1173
Cards
AtlasPPP6R3ID54550ch11q13
Entrez_Gene (NCBI)PPP6R3    protein phosphatase 6 regulatory subunit 3
AliasesC11orf23; PP6R3; SAP190; SAPL; 
SAPLa; SAPS3
GeneCards (Weizmann)PPP6R3
Ensembl hg19 (Hinxton)ENSG00000110075 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000110075 [Gene_View]  ENSG00000110075 [Sequence]  chr11:68460752-68615333 [Contig_View]  PPP6R3 [Vega]
ICGC DataPortalENSG00000110075
TCGA cBioPortalPPP6R3
AceView (NCBI)PPP6R3
Genatlas (Paris)PPP6R3
SOURCE (Princeton)PPP6R3
Genetics Home Reference (NIH)PPP6R3
Genomic and cartography
GoldenPath hg38 (UCSC)PPP6R3  -     chr11:68460752-68615333 +  11q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PPP6R3  -     11q13.2   [Description]    (hg19-Feb_2009)
GoldenPathPPP6R3 - 11q13.2 [CytoView hg19]  PPP6R3 - 11q13.2 [CytoView hg38]
ImmunoBaseENSG00000110075
Genome Data Viewer NCBIPPP6R3 [Mapview hg19]  
OMIM610879   
Gene and transcription
Genbank (Entrez)AB046778 AF264779 AF264780 AK001920 AK023950
RefSeq transcript (Entrez)NM_001164160 NM_001164161 NM_001164162 NM_001164163 NM_001164164 NM_001352347 NM_001352348 NM_001352350 NM_001352351 NM_001352352 NM_001352353 NM_001352354 NM_001352355 NM_001352356 NM_001352357 NM_001352358 NM_001352359 NM_001352360 NM_001352361 NM_001352362 NM_001352363 NM_001352364 NM_001352365 NM_001352366 NM_001352368 NM_001352369 NM_001352370 NM_001352371 NM_001352372 NM_001352373 NM_001352374 NM_001352375 NM_001352376 NM_001352377 NM_001352378 NM_001352379 NM_001352380 NM_018312
Consensus coding sequences : CCDS (NCBI)PPP6R3
Gene ExpressionPPP6R3 [ NCBI-GEO ]   PPP6R3 [ EBI - ARRAY_EXPRESS ]   PPP6R3 [ SEEK ]   PPP6R3 [ MEM ]
Gene Expression Viewer (FireBrowse)PPP6R3 [ Firebrowse - Broad ]
GenevisibleExpression of PPP6R3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)55291
GTEX Portal (Tissue expression)PPP6R3
Human Protein AtlasENSG00000110075-PPP6R3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)PPP6R3
Human Protein Atlas [tissue]ENSG00000110075-PPP6R3 [tissue]
HPRD10703
Protein Interaction databases
BioGRIDPPP6R3
STRING (EMBL)PPP6R3
ZODIACPPP6R3
Ontologies - Pathways
Litterature
PubMed93 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXPPP6R3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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