PPP6R3 (protein phosphatase 6 regulatory subunit 3)

2019-03-01 Luigi Cristiano, MSc Affiliation

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

Identity

HGNC

PPP6R3

LOCATION

11q13.2

LOCUSID

55291

ALIAS

C11orf23,PP6R3,SAP190,SAPL,SAPLa,SAPS3

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.

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_018312	ENST00000265636.9	23	protein coding	4992	Isoform 5	-	NP_060782	793	88.95	4.49
PPP6R3-202 (PPP6R3-021)	Var.44	NR_147968.1	ENST00000265637.8	22	ncRNA	5124	-	-	-	-	-	-
PPP6R3-203 (PPP6R3-001)	Var.6	NM_001164161	ENST00000393800.6	24	protein coding	5127	Isoform 6	-	NP_001157633	873	97.67	4.50
	Var.21	NM_001352361				4873	Isoform 18	-	NP_001339290	782	86.88	4.52
	Var.28	NM_001352368				5211	Isoform 6	-	NP_001339297	873	97.67	4.50
	Var. 35	NM_001352375				5233	Isoform 6	-	NP_001339304	873	97.67	4.50
	Var.41	NR_147965			ncRNA	4942	-	-	-	-	-	-
	Var.43	NR_147967				5401	-	-	-	-	-	-
	Var.45	NR_147969				5235	-	-	-	-	-	-
	Var.46	NR_147970				4978	-	-	-	-	-	-
	Var.47	NR_147971				5362	-	-	-	-	-	-
PPP6R3-204 (PPP6R3-005)	Var.4	NM_001164160	ENST00000393801.7	25	protein coding	5145	Isoform 4	A, C11orf23a, SAPLa	NP_001157632	879	98.49	4.54
	Var.7	NM_001352347				5052	Isoform 7	-	NP_001339276	664	73.15	4.44
	Var.10	NM_001352350				5037	Isoform 8	-	NP_001339279	850	95.26	4.55
	Var.12	NM_001352352				5073	Isoform 10	-	NP_001339281	862	96.45	4.55
	Var.13	NM_001352353				4704	Isoform 11	-	NP_001339282	717	79.53	4.49
	Var.14	NM_001352354				5281	Isoform 12	-	NP_001339283	889	99.47	4.53
	Var.16	NM_001352356				5154	Isoform 12	-	NP_001339285	889	99.47	4.53
	Var.20	NM_001352360				5194	Isoform 17	-	NP_001339289	860	96.25	4.54
	Var.24	NM_001352364				5251	Isoform 4	A, C11orf23a, SAPLa	NP_001339293	879	98.49	4.54
	Var.29	NM_001352369				5149	Isoform 20	-	NP_001339298	654	72.16	4.45
	Var.30	NM_001352370				4891	Isoform 21	-	NP_001339299	788	87.69	4.56
	Var.31	NM_001352371				5200	Isoform 10	-	NP_001339300	862	96.45	4.55
	Var.32	NM_001352372				5233	Isoform 24	-	NP_001339301	873	97.73	4.54
	Var.33	NM_001352373				5067	Isoform 17	-	NP_001339302	860	96.25	4.54
	Var.34	NM_001352374				4804	Isoform 22	-	NP_001339303	759	84.47	4.58
	Var.36	NM_001352376				5164	Isoform 8	-	NP_001339305	850	95.26	4.55
	Var.37	NM_001352377				5106	Isoform 24	-	NP_001339306	873	97.73	4.54
	Var.38	NM_001352378				4931	Isoform 22	-	NP_001339307	759	84.47	4.58
	Var.39	NM_001352379				5390	Isoform 4	A, C11orf23a, SAPLa	NP_001339308	879	98.49	4.54
	Var.40	NM_001352380				5142	Isoform 8	-	NP_001339309	850	95.26	4.55
	Var.42	NR_147966			ncRNA	5392	-	-	-	-	-	-
PPP6R3-205 (PPP6R3-026)	Var.2	NM_001164163	ENST00000524845.5	23	protein coding	5040	Isoform 2	-	NP_001157635	844	94.44	4.51
	Var.15	NM_001352355				4786	Isoform 13	-	NP_001339284	753	83.65	4.54
	Var.23	NM_001352363				5146	Isoform 2	-	NP_001339292	844	94.44	4.51
PPP6R3-206 (PPP6R3-007)	Var.1	NM_001164162	ENST00000524904.5	24	protein coding	5109	Isoform 1	-	NP_001157634	867	96.96	4.51
	Var.8	NM_001352348				5284	Isoform 1	-	NP_001339277	867	96.96	4.51
	Var.11	NM_001352351				4822	Isoform 9	-	NP_001339280	765	84.84	4.54
	Var.18	NM_001352358				4902	Isoform 15	-	NP_001339287	805	90.14	4.49
	Var.19	NM_001352359				4885	Isoform 16	-	NP_001339288	786	87.15	4.52
	Var.22	NM_001352362				5129	Isoform 19	-	NP_001339291	856	95.63	4.52
	Var.25	NM_001352365				5055	Isoform 19	-	NP_001339294	856	95.63	4.52
PPP6R3-207	-	-	ENST00000525050.5	4	retained intron	513	-	-	-	-	-	-
PPP6R3-208	-	-	ENST00000525152.1	2	retained intron	582	-	-	-	-	-	-
PPP6R3-209	-	-	ENST00000525421.5	8	nonsense md	830	-	-	-	-	-	-
PPP6R3-210	-	-	ENST00000526307.5	10	retained intron	4134	-	-	-	-	-	-
PPP6R3-211	-	-	ENST00000526574.1	4	retained intron	489	-	-	-	-	-	-
PPP6R3-212	-	-	ENST00000526593.1	5	nonsense md	570	-	-	-	-	-	-
PPP6R3-213	-	-	ENST00000527069.5	4	retained intron	573	-	-	-	-	-	-
PPP6R3-214 (PPP6R3-020)	Var.26	NM_001352366	ENST00000527403.6	22	protein coding	5019	Isoform 23	-	NP_001339295	844	94.55	4.56
PPP6R3-215 (PPP6R3-012)	-	-	ENST00000528635.5	5	(?)	538	-	-	-	-	-	-
PPP6R3-216	-	-	ENST00000529172.1	4	retained intron	500	-	-	-	-	-	-
PPP6R3-217 (PPP6R3-011)	-	-	ENST00000529344.5	4	(?)	603	-	-	-	-	-	-
PPP6R3-218 (PPP6R3-004)	Var.3	NM_001164164	ENST00000529710.5	23	protein coding	3426	Isoform 3	B, C11orf23b, SAPLb	NP_001157636	791	88.91	4.48
PPP6R3-219 (PPP6R3-009)	-	-	ENST00000529907.5	7	(?)	826	-	-	-	-	-	-
PPP6R3-220	-	-	ENST00000530427.5	5	processed transcript	560	-	-	-	-	-	-
PPP6R3-221 (PPP6R3-025)	-	-	ENST00000530734.1	2	(?)	576	-	-	-	-	-	-
PPP6R3-222 (PPP6R3-013)	-	-	ENST00000531244.1	5	(?)	687	-	-	-	-	-	-
PPP6R3-223	-	-	ENST00000531432.1	2	retained intron	590	-	-	-	-	-	-
PPP6R3-224 (PPP6R3-027)	-	-	ENST00000533127.5	4	(?)	551	-	-	-	-	-	-
PPP6R3-225 (PPP6R3-018)	Var.17	NM_001352357	ENST00000534190.5	16	protein coding	5150	Isoform 14	-	NP_001339286	619	68.12	4.42
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.

Proteins

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

Organism	Species	Symbol	DNA Identity (%)	Prot Identity (%)
Human	H.sapiens	PPP6R3	100	100
Chimpanzee	P.troglodytes	LOC710120	99.6	99.8
Macaco	M.mulatta	PPP6R3	95.6	96.4
Wolf	C.lupus	PPP6R3	92.8	92.2
Cattle	B.taurus	PPP6R3	91.8	96.0
Mouse	M.musculus	Ppp6r3	90.5	96.3
Rat	R.norvegicus	Ppp6r3	90.6	95.5
Chicken	G.gallus	PPP6R3	82.8	91.5
Xenopus tropicalis	X.tropicalis	Ppp6r3	75.6	80.3
Zebrafish	D.rerio	Ppp6r3	71.6	79.0

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

Implicated in

Top 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.
RNF121/PPP6R3	RNF121	PPP6R3	11q13.4	11q13.2	t(11;11)(q13;q13)	Fusion gene	Adenocarcinoma	Breast	BRCA	Yoshihara et al., 2015
VPS50/PPP6R3	VPS50	PPP6R3	7q21.3	11q13.2	t(7;11)(q21;q13)	Translocation	(?)	(?)	(?)	-

Chronic myeloid leukemiaBloodCMLStopera et al., 1990 TNFRSF21/PPP6R3TNFRSF21PPP6R3 6p12.3 11q13.2t(6;11)(p12;q13)TranslocationAdenocarcinomaBreastBRCABanerji et al., 2012 PPP6R3/YAP1PPP6R3YAP111q13.211q22.1 t(11;11)(q13;q22)Fusion gene Transitional cell carcinomaBladderBLCAYoshihara et al., 2015 PPP6R3/EIF4G3PPP6R3EIF4G311q13.2 1p36.12t(1;11)(p36;q13)TranslocationMalignant melanomaSkinSKCM- NADSYN1/PPP6R3NADSYN1PPP6R3 11q13.411q13.2t(11;11)(q13;q13)Fusion geneMalignant melanomaSkinSKCMHu et al., 2018; Klijn et al., 2015 PPP6R3/MTL5PPP6R3MTL511q13.211q13.3 t(11;11)(q13;q13)Fusion geneAdenocarcinomaBreastBRCAYoshihara et al., 2015 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/SSH2PPP6R3SSH211q13.217q11.2t(11;17)(q13;q11)TranslocationAdenocarcinomaBreastBRCAYoshihara et al., 2015 TMPRSS6/PPP6R3TMPRSS6PPP6R3 22q12.311q13.2t(11;22)(q13;q12)TranslocationLiver hepatocellular carcinomaLiver LIHC- PPP6R3/USP6 PPP6R3USP6 11q13.2 17p13.2 t(11;17)(q13;p13) TranslocationNodular fasciitisSoft tissueNFGuo et al., 2016 Multiple myelomaBloodMMSawyer et al., 1995; Sawyer et al., 2014 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 name

Acute lymphoblastic leukemia (ALL)

Hybrid 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 name

Bladder cancer

Hybrid 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 name

Breast cancer

Hybrid 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 name

Cervical carcinoma

Hybrid gene

A t(11;15)(q13;q22) RAB11A/PPP6R3 has been found in cervical carcinoma (http://www.tumorfusions.org).

Entity name

Gastric cancer

Hybrid gene

The fusion gene PPP6R3/ RHOD has been found in gastric adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)

Entity name

t(11;17)(q13;p13)PPP6R3/USP6 in hematological malignancies.

Hybrid 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 name

Hepatocellular carcinoma

Hybrid gene

A t(11;22)(q13;q12) TMPRSS6/PPP6R3 has been found in hepatocellular carcinoma (http://www.tumorfusions.org).

Entity name

Lung squamous cell carcinoma

Hybrid 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 name

Malignant melanoma

Hybrid 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 name

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 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 name

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 name

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 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).

Fusion 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 name

Pancreatic cancer

Hybrid gene

The fusion genes PPP6R3/LRP5 and PPP6R3/ SSH3 have been found in pancreas adenocarcinoma (Hu et al., 2018; http://www.tumorfusions.org)

Entity name

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 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.

Fusion 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 name

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 name

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).

Bibliography

Pubmed ID	Last Year	Title	Authors
22722202	2012	Sequence analysis of mutations and translocations across breast cancer subtypes.	Banerji S et al
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27113271	2016	PPP6R3-USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis.	Guo R et al
26659575	2016	Identification of Novel Fusion Genes in Testicular Germ Cell Tumors.	Hoff AM et al
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1394107	1992	Complex chromosomal rearrangements in an unusual variant of hairy cell leukemia.	Nacheva E et al
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Other Information

Locus ID:

NCBI: 55291
MIM: 610879
HGNC: 1173
Ensembl: ENSG00000110075

Variants:

dbSNP: 55291
ClinVar: 55291
TCGA: ENSG00000110075
COSMIC: PPP6R3

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000110075	ENST00000265636	Q5H9R7
ENSG00000110075	ENST00000265636	A0A024R5F3
ENSG00000110075	ENST00000265637	H7BXH2
ENSG00000110075	ENST00000393800	Q5H9R7
ENSG00000110075	ENST00000393801	Q5H9R7
ENSG00000110075	ENST00000524845	Q5H9R7
ENSG00000110075	ENST00000524904	Q5H9R7
ENSG00000110075	ENST00000525421	H0YDW1
ENSG00000110075	ENST00000526593	H0YEV0
ENSG00000110075	ENST00000527403	E9PKF6
ENSG00000110075	ENST00000528635	A0A1D5RMU2
ENSG00000110075	ENST00000529344	E9PKG4
ENSG00000110075	ENST00000529710	Q5H9R7
ENSG00000110075	ENST00000529907	E9PK08
ENSG00000110075	ENST00000530734	H0YDK9
ENSG00000110075	ENST00000531244	E9PNN8
ENSG00000110075	ENST00000533127	E9PJD8
ENSG00000110075	ENST00000534190	H0YEN2
ENSG00000110075	ENST00000534534	E9PQP7

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Asparagine N-linked glycosylation	REACTOME	R-HSA-446203
Transport to the Golgi and subsequent modification	REACTOME	R-HSA-948021
ER to Golgi Anterograde Transport	REACTOME	R-HSA-199977
COPII (Coat Protein 2) Mediated Vesicle Transport	REACTOME	R-HSA-204005
Vesicle-mediated transport	REACTOME	R-HSA-5653656
Membrane Trafficking	REACTOME	R-HSA-199991

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
31904830	2020	Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase.	2
31904830	2020	Protein kinase CK2 phosphorylation of SAPS3 subunit increases PP6 phosphatase activity with Aurora A kinase.	2
28893231	2017	Involvement of DPP9 in gene fusions in serous ovarian carcinoma.	13
28893231	2017	Involvement of DPP9 in gene fusions in serous ovarian carcinoma.	13
27113271	2016	PPP6R3-USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis.	12
27113271	2016	PPP6R3-USP6 amplification: Novel oncogenic mechanism in malignant nodular fasciitis.	12
26288249	2015	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development.	25
26288249	2015	Variability of Gene Expression Identifies Transcriptional Regulators of Early Human Embryonic Development.	25

Citation

Luigi Cristiano

PPP6R3 (protein phosphatase 6 regulatory subunit 3)

Atlas Genet Cytogenet Oncol Haematol. 2019-03-01

Online version: http://atlasgeneticsoncology.org/gene/54550/ppp6r3