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PARK2 (Parkin RBR E3 ubiquitin protein ligase)

Written2015-12Valentina La Cognata, Sebastiano Cavallaro
Functional Genomics Unit - Institute of Neurogical Sciences - Italian National Research Council - Catania- Italy. sebastiano.cavallaro@cnr.it; valentina.lacognata@functional-genomics.it

Abstract PARK2 (also known as Parkin RBR E3 ubiquitin protein ligase) is one of the largest genes in our genome. It undergoes an extensive alternative splicing both at transcript and protein level, producing multiple transcript variants and distinct protein isoforms. The precise function of PARK2 is still not clear; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrates for proteasomal degradation. Mutations in this gene cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Further molecular defects have been linked to other human malignancies. Here, we review some major data on PARK2, concerning the genetic structure, the transcription regulation, the encoded protein and functions, and its implication in human diseases.

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Identity

Alias_namesParkinson disease (autosomal recessive, juvenile) 2, parkin
parkinson protein 2, E3 ubiquitin protein ligase (parkin)
Alias_symbol (synonym)PDJ
AR-JP
parkin
HGNC (Hugo) PARK2
LocusID (NCBI) 5071
Atlas_Id 46408
Location 6q26  [Link to chromosome band 6q26]
Location_base_pair Starts at 161768590 and ends at 163148834 bp from pter ( according to hg19-Feb_2009)  [Mapping PARK2.png]
Local_order PARK2 is flanked towards the telomeric direction by PACRG (or PARK2 co-regulated) gene, which lies in a head-to-head arrangement and shares a common promoter with the adjacent PARK2 (West et al., 2003). In the centromeric direction PARK2 is flanked by AGPAT4 (1-acylglycerol-3-phosphate O-acyltransferase), which encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. According to NCBI MapViewer, further elements overlap or surround the PARK2 genetic region, such as two pseudogenes (KRT8P44 and TRE-TTC15-1) and a set of non-coding RNAs (LOC105378094, LOC105378098, LOC105378097 and LOC105369171).
 
  Figure 1 displays the human chromosome 6 (NCBI Reference Sequence NC_000006.12) and relative localization and orientation of PARK2 and flanking genes. PARK2 gene is represented in blue and is transcribed in antisense orientation (reverse strand). Further genes and non-coding RNAs map in this locus.

DNA/RNA

 
  Figure 2 displays the three full-length Reference Sequences of PARK2 gene (NCBI - Nucleotide Database). Corresponding GenBank Accession Numbers are indicated on the left. Exons are represented as coloured boxes (blue for coding regions and grey for non coding), whereas the dashed line indicates intronic regions. The green triangle specifies the start codon, while the red one designates the stop codon.
 
Description PARK2 is one of the largest genes in the human genome, and spans more than 1.38 Mb of genomic DNA in the long arm of chromosome 6 (reverse strand). Based on the first isolated transcript, the genomic organization and exon/intron boundary sequences of PARK2 were established of 12 exons.
Transcription Currently, the NCBI RefSeq database annotates 3 representative transcripts as full-length PARK2 mRNAs (Figure 2). However, Homo sapiens cDNA sequences deposited in GenBank and UniGene repositories, coaligned on the genomic sequence and clustered in a minimal non-redundant way, support at least 21 different alternatively spliced mRNAs composed by 17 exons (Figure 3) (La Cognata et al., 2014; Scuderi et al., 2014). Each of these splice variants is indicated in Table 1.

Gene

#mRNA

Acc.Num.

Transcript Length

PARK2

1.

NM_004562.2

4073 bp

2.

AF381282.1

1157 bp

3.

AF381284.1

1158 bp

4.

BC022014.2

1575 bp

5.

NM_013987.2

3989 bp

6.

NM_013988.2

3626 bp

7.

AK294684.1

1115 bp

8.

GU345837.1

1298 bp

9.

GU345838.1

1340 bp

10.

GU345840.1

1313 bp

11.

GU357501.1

936 bp

12.

GU357502.1

873 bp

13.

GU361466.1

1279 bp

14.

GU361467.1

1229 bp

15.

GU361468.1

1010 bp

16.

GU361469.1

1559 bp

17.

GU361470.1

1561 bp

18.

GU361471.1

634 bp

19.

KC357594.1

454 bp

20.

KC357595.1

1627 bp

21.

KC774171.1

1282 bp

Pseudogene No known pseudogenes.

Protein

 
  Figure 4 shows the domain composition of PARK2 protein, obtained from SMART Genome tool (http://smart.embl.de/). UBQ is the N-term ubiquitin domain, while IBRs are the C-term in-between ring fingers domains. In Table 2 are reported the aminoacidic start and stop positions and the E-value of the domain prediction.
Description The canonical PARK2 protein (Accession number BAA25751.1) (465 aa) comprises an N-terminal ubiquitin-like (UBQ) domain and two C-terminal in-between ring fingers (IBR) domains (Kitada et al., 1998). The UBQ domain targets specific protein substrates for degradation by the proteasome, whereas IBR domains occur between pairs of ring fingers and play a role in protein quality control (Figure 4). The predicted PARK2 protein isoforms, encoded by the alternative splice transcripts currently known, structurally diverge from the canonic one for the presence or absence of the UBQ domain and for one or both IBR domains. Moreover, when UBQ domain is present, it often differs in length from the canonical one (La Cognata et al, 2014: Scuderi et al., 2014).

Domain

Start

Stop

E-value

UBQ

1

72

2.95e-16

IBR

313

377

4.49e-14

IBR

401

457

0.142

 
  Figure 5 (adapted from Scuderi et al., 2014) shows a representative immunoblot of parkin protein isoforms in homogenized rat brain, visualized by using five different antibodies (Ab1, Ab2, Ab3, Ab4, Ab5). Immunoblot for β-tubulin is used as control. The right panel of the figure shows the localization of the epitopes recognized by the five antibodies on the canonical parkin protein.
Expression PARK2 is widely expressed in a variety of tissue types, including nervous system areas (brain, substantia nigra, mesencephalon, cerebellum, frontal cortex, striatum) (Shimura et al., 2001; Schlossmacher et al., 2002; LaVoie et al., 2005; Sun et al., 2013) and peripheral regions (skeletal muscle, heart and testicular tissue) (Kitada et al., 1998; Rosen et al., 2006), as well as in immortalized cell lines (neuroblastoma, kidney, epithelial, breast cancer and colon cancer cell lines) (Yamamoto et al., 2005; Henn et al., 2007; Poulogiannis et al., 2010; Tay et al., 2010). In addition, distinct expression patterns of the PARK2 spliced isoforms have emerged in human leukocytes (Kasap et al., 2009), glioma and lung adenocarcinoma cell lines (D'Amico et al., 2015; Maugeri et al., 2015) and aged brain (Pawlyk et al., 2003). The differential expression of PARK2 splice isoforms have also observed in rat and mouse central and peripheral tissues and developmental stages (Horowitz et al., 1999; D'Agata et al., 2000; Gu et al., 2000; Stichel et al., 2000; Huynh et al., 2001).
 
  Figure 6 (adapted from Maugeri et al., 2015) shows the immunolocalization of parkin protein in glioblastoma cell lines (A172 cells). β-actin (red) was used as control and nuclei were stained with DAPI (blue).
Localisation Subcellular localisation: PARK2 is mainly cytoplasmatic (Figure 5). Positive signals have been detected in endoplasmic reticulum (Imai et al., 2002), perinuclear region, microtubules (Ren et al., 2003), nucleus and plasma membrane. PARK2 protein also colocalizes with Lewy bodies (Schlossmacher et al., 2002), the pathological hallmark of Parkinson's Disease and dementia.
 
  Figure 7 shows the major pathways in which PARK2 protein is involved: proteasome-degradation of substrates, mitochondrial homeostasis and mitophagy, and regulation of cellular cycle and cell death.
Function PARK2 protein acts as an E3 ubiquitin protein ligase and is responsible of substrates recognition for proteasome-mediated degradation. It tags various types of proteins, including cytosolic ( SNCAIP (Synphilin-1), GPR37 (Pael-R), SEPT5 (CDCrel-1) and 2a, SNCA ID: 46121> (α-synuclein), p22, Synaptogamina XI) (Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000; Chung et al., 2001; Staropoli et al., 2003), nuclear (Cyclin E, Cyclin D) (Ikeuchi et al., 2009; Gong et al., 2014) and mitochondrial ones (MFN1 and MFN2, VDAC, TOMM70A, TOMM40 and TOMM0, BAK1, RHOT1 (MIRO1) and RHOT2 (MIRO2), FIS1) (Narendra et al., 2008; Chan et al., 2011; Yoshii et al., 2011; Cookson, 2012; Jin et al., 2012). The number of targets is such high that parkin protein results involved in numerous molecular pathways (proteasome-degradation, mitochondrial homeostasis, mitophagy, mitochondrial DNA stability, regulation of cellular cycle).
 
  Figure 8 shows the evolutionary PARK2 Gene Tree, constructed using the multiple genome comparison tool PhyloView of Genomicus v.82.01 (http://www.genomicus.biologie.ens.fr/). This tool compares a specific gene with all the genomes that possess a homolog (Louis et al., 2015). Mammalia taxon has been defined as the root of the tree. PARK2 gene is displayed and highlighted in the central part of the figure. The internal nodes of the phylogenetic tree are represented as red boxes for duplication and blue boxes for speciation events. The percentage of similarity of homologous proteins is represented with different colours, as indicated in the legend.
Homology PARK2 gene shows a great evolutionary conservation across species, especially mammals. Mouse and rat species represent the most common animals used to model and study human pathologies. Human PARK2 protein shows a protein similarity of about 50% with rat, while it is more similar with the mouse parkin (90% of similarity) (protein similarity is calculated used Genomicus - PhyloView tool) (Figure 8).

Mutations

 
  Figure 9 shows the overall distribution of PARK2 somatic mutations in cancer listed in COSMIC Database (http://cancer.sanger.ac.uk/cosmic) (November 2015). The exact number of collected somatic mutations in different cancer types is indicated in Table 3.
Epigenetics Promoter hypermethylation is a common epigenetic mechanism to alter the gene expression. PARK2 promoter hypermethylation has been found in acute lymphoblastic leukemia, chronic myeloid leukemia and colorectal cancer (Agirre et al., 2006; Xu et al., 2014). However, the pathogenic role of specific epigenetic changes has not been yet clarified.
Germinal A wide spectrum of loss-of-function mutations in PARK2 including simple mutations (nonsense, missense and splice site mutations), frameshift indels or in the untraslated regions, as well as Copy Number Variations of the promoter region and single or multiple exons PARK2 mutations, were identified across the entire gene in either homozygous, compound heterozygous or heterozygous state in familial and sporadic patients from different ethnicities. Heterozygous PARK2 variants have also been observed in healthy control individuals, making the assessment of pathogenicity for these variants quite complex. A complete and updated view of all PARK2 currently known mutations is available at the Parkinson Disease Mutation Database (http://www.molgen.vib-ua.be/PDMutDB/), which collects DNA variations screened among more than 800 families and linked to PD.
Somatic Along with the germinal mutations occuring in Parkinson's Disease, genetic defects have also been observed in solid tumors. Based on the analysis of recent next generation sequencing data, the frequency of PARK2 mutations is relatively high in cervical cancer (5.6 %), lung squamous cell cancer (5.6 %), colorectal cancer (2.4 ~ 5.6 %), gastric cancer (4.6 %), skin cutaneous melanoma (3.5 %), lung adenocarcinoma (2.7 ~ 3.1 %), and endometrioid cancer (2.1%) Most cancer-derived PARK2 mutations are located at conserved regions, and more than 10% of mutations lead to frame shifts or truncations, suggesting that those mutations may disrupt or abolish the function of PARK2 (Xu et al., 2014). A list of the known cancer-derived mutations is available at the COSMIC Database and is summarized in Figure 9.

Mutation Type

Mutant samples

Substitution nonsense

6

Substitution missense

105

Substitution synonymous

52

Insertion inframe

0

Insertion frameshift

2

Deletion inframe

0

Deletion frameshift

4

Complex

1

Other

0

Implicated in

Note
Entity Parkinson's Disease
Note Mutations in PARK2 are responsible of 50% of cases with autosomal recessive juvenile Parkinsonism (AR-JP). They also explain ~15% of the sporadic cases with onset before 45 (Lucking et al., 2000; Bonifati, 2012) and act as susceptibility alleles for late-onset forms of Parkinson disease (2% of cases) (Oliveira et al., 2003). Clinical features of PARK2 homozygous mutation carriers are generally indistinguishable from those of idiopathic PD patients with the exception of a clear drop in onset age. Typically PARK2 patients present the classic symptoms of PD (such as bradykinesia, rigidity, and tremor), disease onset before the age of 50 years and a slow disease progression. Although they respond well to levodopa treatment, they are more likely to develop treatment-induced motor complications earlier in the treatment (Nuytemans et al., 2010).
  
Entity Alzheimer Disease
Note Lonskaya and colleagues investigated the role of parkin in postmortem brain tissues from 21 patients with Alzheimer Disease (AD) and 15 control subjects. They observed decreased parkin solubility in cortex of patients and parkin co-localization with intraneuronal amyloid-beta depositions (Aβ1-42) in the hippocampus and cortex. Parkin accumulation with intraneuronal Aβ and p-Tau was detected in autophagosomes in AD brains. By using a gene transfer animal model, the authors also demonstrated that the expression of wild type parkin facilitate autophagic clearance and promoted deposition of Aβ1-42 and p-Tau into the lysosome (Lonskaya et al., 2013). Parkin, therefore, may clear autophagic defects via autophagosome degradation.
  
Entity Leprosy
Note Using a positional cloning strategy in 197 Vietnamese leprosy simplex families, Mira et al. found significant associations between leprosy and 17 markers in the 5-prime regulatory region shared by PARK2 and PACRG. They then confirmed these results in 587 Brazilian leprosy cases and 388 unaffected controls. RT-PCR analysis detected wide expression of both PARK2 and PACRG in tissues, and suggested that, in addition to the common bidirectional promoter, gene-specific transcriptional activators may be involved in regulating cell- and tissue-specific gene expression (Mira et al., 2004). In 2013, Alter et al. replicated these findings showing a susceptibility locus in the shared PARK2 and PACRG promoter region in a Vietnamese population. They also found that two SNPs (rs1333955 and rs2023004) were associated with susceptibility to leprosy in a northern Indian population (Alter et al., 2013).
  
Entity Gliomas
Note Veeriah et al. provided evidence that PARK2 acts as a tumour suppressor gene in glioblastoma multiforme. Genetically, they detected PARK2 copy number loss in 53 of 216 glioblastomas and somatic point mutations in 7 glioblastomas specimens (Veeriah et al., 2010). The action of tumour suppressor gene for gliomas has been furthermore described by Yeo et al., who found parkin expression dramatically reduced in glioma cells, while its restoration promoted G(1) phase cell-cycle arrest and mitigated the proliferation rate (Yeo et al., 2012). Authors suggested the analysis of parkin pathway activation as predictive for the survival outcome of patients with glioma. The effects of PARK2 on tumour cell growth were also confirmed by Lin et al., who reported that PARK2 is frequently deleted and underexpressed in human gliomas, and that restoration of PARK2 significantly inhibited glioma cell growth (Lin et al., 2015).
An interesting transcriptional target of parkin is p53. Viotti et al. were able to demonstrate that parkin levels inversely correlate to brain tumour grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas, and established that p53 controls parkin promoter transactivation, mRNA and protein levels (Viotti et al., 2014).
  
Entity Colon cancer
Note Microarray analysis revealed copy number loss in 24 of 98 colon cancers and different PARK2 somatic point mutations in 2 colon cancer cells lines (Veeriah et al., 2010). Additionally, in 100 primary colorectal carcinomas, Poulogiannis et al. demonstrated by array comparative genomic hybridization that 33% show PARK2 copy number loss (Poulogiannis et al., 2010). The PARK2 deletions are mostly focal, heterozygous, and show maximum incidence in exons 3 and 4. Deficiency in expression of PARK2 is significantly associated also with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Moreover, in the same study, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity.
  
Entity Lung adenocarcinoma
Note Somatic homozygous deletions of exon 2 of the PARK2 gene were found in 2 lung adenocarcinoma cell lines, Calu-3 and H-1573, suggesting that the loss of this locus and the resulting changes in its expression are involved in the development of the tumour (Cesari et al., 2003). Additional germline and somatic deletions were also reported by Iwakawa et al. in five patients with lung adenocarcinoma and in 31/267 lung adenocarcinoma, indicating that somatic PARK2 mutations occur rarely in lung adenocarcinoma development, but germline mutations could contribute to tumour progression (Iwakawa et al., 2012). Very recently, Xiong et al. reported the PARK2 germline mutation c.823C>T (p.Arg275Trp) in a family with eight cases of lung cancer (Xiong et al., 2015).
  
Entity Ovarian Cancer
Note Two different groups identified both PARK2 genetic alterations and downregulated expression in ovarian cancer. Cesari et al. detected two PARK2 truncating deletions in 3 of 20 ovarian tumour samples, supporting the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of PARK2 in tumour biopsies and tumour cell lines. They suggest that PARK2 may act as a tumour suppressor gene and may contribute to the initiation and/or progression of ovarian cancer (Cesari et al., 2003). Denison et al. found four cell lines and four primary tumours as heterozygous for the duplication or deletion of a Parkin exon. The analysis of Parkin protein expression revealed that most of the ovarian cancer cell lines and primary tumours had diminished or absent Parkin expression (Denison et al., 2003).
  
Entity Other malignancies
Note Alterations or molecular defects involving the coding region of the gene (single nucleotide mutations, copy numbers, gene breakage), epigenetic mechanisms, the mRNA up or down regulation, the protein level and the abnormal splicing of PARK2 have been linked to a wide range of other human malignancies (i.e. acute lymphoblastic leukemia, chronic myeloid leukemia, clear cell renal cell carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, gastric cancer, pancreatic adenocarcinoma, breast cancer, bladder urothelial cancer, thyroid cancer, adenoid cystic carcinoma) (Xu et al., 2014).
  

Breakpoints

 
  Figure 10 (adapted from Ambroziak et al., 2015) shows the hypothesized mechanism of the Ex2-5 duplication observed in a patient with early-onset PD. The authors suggest the FoSTeS/MMBIR (fork stalling and template switching/micro-homology-mediated break-induced replication) mechanism as responsible of the rearrangement. Upon replicating, the first exon of the PARK2 gene replication fork stalled and one strand invaded either the sister molecule or the homologue chromosome in inverted orientation (1), resulting in inverted duplication. Subsequently, the original forks were restored, but primed upstream of the point where it first stalled (2), leading to the triplication of the red-highlighted region (Ambroziak et al., 2015).
Note PARK2 belongs to the family of extremely large human genes and is located within FRA6E, one of the most unstable common fragile sites (CFSs) of the human genome. CFSs are intrinsically difficult to replicate, and are known to play a major role in carcinogenesis. Some factors have been considered to contribute to instabilities, including late-replicating genomic regions, high AT content, flexible DNA sequences or regions enriched in repetitive elements. The exact size of the region of instability of FRA6E is not yet clear; however, it has been suggested that it may span even 9 Mb at 6q25.1-6q26 and that the main fragility core is localised on the telomeric end, within the PARK2 gene sequence. The most common molecular mechanisms which seem predominantly involved in the rearrangement processes of this genomic region are non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/micro-homology mediated break-induced replication (MMBIR) (Figure 10) (Ambroziak et al., 2015).

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PMID 20506312
 
Parkin mutations and susceptibility alleles in late-onset Parkinson's disease
Oliveira SA, Scott WK, Martin ER, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia F, Stajich JM, Zhang F, Booze MW, Winn MP, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM
Ann Neurol 2003 May;53(5):624-9
PMID 12730996
 
Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age
Pawlyk AC, Giasson BI, Sampathu DM, Perez FA, Lim KL, Dawson VL, Dawson TM, Palmiter RD, Trojanowski JQ, Lee VM
J Biol Chem 2003 Nov 28;278(48):48120-8
PMID 12972409
 
PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice
Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ
Proc Natl Acad Sci U S A 2010 Aug 24;107(34):15145-50
PMID 20696900
 
Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation
Ren Y, Zhao J, Feng J
J Neurosci 2003 Apr 15;23(8):3316-24
PMID 12716939
 
Parkin protects against mitochondrial toxins and beta-amyloid accumulation in skeletal muscle cells
Rosen KM, Veereshwarayya V, Moussa CE, Fu Q, Goldberg MS, Schlossmacher MG, Shen J, Querfurth HW
J Biol Chem 2006 May 5;281(18):12809-16
PMID 16517603
 
Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies
Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Sharon R, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik KS
Am J Pathol 2002 May;160(5):1655-67
PMID 12000718
 
Alternative splicing generates different parkin protein isoforms: evidences in human, rat, and mouse brain
Scuderi S, La Cognata V, Drago F, Cavallaro S, D'Agata V
Biomed Res Int 2014;2014:690796
PMID 25136611
 
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Shimura H, Hattori N, Kubo Si, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T
Nat Genet 2000 Jul;25(3):302-5
PMID 10888878
 
Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease
Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ
Science 2001 Jul 13;293(5528):263-9
PMID 11431533
 
Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity
Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A
Neuron 2003 Mar 6;37(5):735-49
PMID 12628165
 
Parkin expression in the adult mouse brain
Stichel CC, Augustin M, Kühn K, Zhu XR, Engels P, Ullmer C, Lübbert H
Eur J Neurosci 2000 Dec;12(12):4181-94
PMID 11122330
 
ATF4 protects against neuronal death in cellular Parkinson's disease models by maintaining levels of parkin
Sun X, Liu J, Crary JF, Malagelada C, Sulzer D, Greene LA, Levy OA
J Neurosci 2013 Feb 6;33(6):2398-407
PMID 23392669
 
Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells
Tay SP, Yeo CW, Chai C, Chua PJ, Tan HM, Ang AX, Yip DL, Sung JX, Tan PH, Bay BH, Wong SH, Tang C, Tan JM, Lim KL
J Biol Chem 2010 Sep 17;285(38):29231-8
PMID 20630868
 
Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies
Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA
Nat Genet 2010 Jan;42(1):77-82
PMID 19946270
 
Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity
Viotti J, Duplan E, Caillava C, Condat J, Goiran T, Giordano C, Marie Y, Idbaih A, Delattre JY, Honnorat J, Checler F, Alves da Costa C
Oncogene 2014 Apr 3;33(14):1764-75
PMID 23644658
 
Identification of a novel gene linked to parkin via a bi-directional promoter
West AB, Lockhart PJ, O'Farell C, Farrer MJ
J Mol Biol 2003 Feb 7;326(1):11-9
PMID 12547187
 
A recurrent mutation in PARK2 is associated with familial lung cancer
Xiong D, Wang Y, Kupert E, Simpson C, Pinney SM, Gaba CR, Mandal D, Schwartz AG, Yang P, de Andrade M, Pikielny C, Byun J, Li Y, Stambolian D, Spitz MR, Liu Y, Amos CI, Bailey-Wilson JE, Anderson M, You M
Am J Hum Genet 2015 Feb 5;96(2):301-8
PMID 25640678
 
An emerging role of PARK2 in cancer
Xu L, Lin DC, Yin D, Koeffler HP
J Mol Med (Berl) 2014 Jan;92(1):31-42
PMID 24297497
 
Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity
Yamamoto A, Friedlein A, Imai Y, Takahashi R, Kahle PJ, Haass C
J Biol Chem 2005 Feb 4;280(5):3390-9
PMID 15557340
 
Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival
Yeo CW, Ng FS, Chai C, Tan JM, Koh GR, Chong YK, Koh LW, Foong CS, Sandanaraj E, Holbrook JD, Ang BT, Takahashi R, Tang C, Lim KL
Cancer Res 2012 May 15;72(10):2543-53
PMID 22431710
 
Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane
Yoshii SR, Kishi C, Ishihara N, Mizushima N
J Biol Chem 2011 Jun 3;286(22):19630-40
PMID 21454557
 
Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM
Proc Natl Acad Sci U S A 2000 Nov 21;97(24):13354-9
PMID 11078524
 

Citation

This paper should be referenced as such :
La Cognata V, Cavallaro S
PARK2 (Parkin RBR E3 ubiquitin protein ligase);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/PARK2ID46408ch6q26.html


External links

Nomenclature
HGNC (Hugo)PARK2   8607
Cards
AtlasPARK2ID46408ch6q26.txt
Entrez_Gene (NCBI)PARK2  5071  parkin RBR E3 ubiquitin protein ligase
AliasesAR-JP; LPRS2; PDJ; PRKN
GeneCards (Weizmann)PARK2
Ensembl hg19 (Hinxton)ENSG00000185345 [Gene_View]  chr6:161768590-163148834 [Contig_View]  PARK2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000185345 [Gene_View]  chr6:161768590-163148834 [Contig_View]  PARK2 [Vega]
ICGC DataPortalENSG00000185345
TCGA cBioPortalPARK2
AceView (NCBI)PARK2
Genatlas (Paris)PARK2
WikiGenes5071
SOURCE (Princeton)PARK2
Genetics Home Reference (NIH)PARK2
Genomic and cartography
GoldenPath hg19 (UCSC)PARK2  -     chr6:161768590-163148834 -  6q25.2-q27   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PARK2  -     6q25.2-q27   [Description]    (hg38-Dec_2013)
EnsemblPARK2 - 6q25.2-q27 [CytoView hg19]  PARK2 - 6q25.2-q27 [CytoView hg38]
Mapping of homologs : NCBIPARK2 [Mapview hg19]  PARK2 [Mapview hg38]
OMIM167000   211980   600116   602544   607572   
Gene and transcription
Genbank (Entrez)AB009973 AB245403 AF381282 AF381283 AF381284
RefSeq transcript (Entrez)NM_004562 NM_013987 NM_013988
RefSeq genomic (Entrez)NC_000006 NC_018917 NG_008289 NT_025741 NW_004929328
Consensus coding sequences : CCDS (NCBI)PARK2
Cluster EST : UnigeneHs.132954 [ NCBI ]
CGAP (NCI)Hs.132954
Alternative Splicing GalleryENSG00000185345
Gene ExpressionPARK2 [ NCBI-GEO ]   PARK2 [ EBI - ARRAY_EXPRESS ]   PARK2 [ SEEK ]   PARK2 [ MEM ]
Gene Expression Viewer (FireBrowse)PARK2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5071
GTEX Portal (Tissue expression)PARK2
Protein : pattern, domain, 3D structure
UniProt/SwissProtO60260   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO60260  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO60260
Splice isoforms : SwissVarO60260
Catalytic activity : Enzyme6.3.2.- [ Enzyme-Expasy ]   6.3.2.-6.3.2.- [ IntEnz-EBI ]   6.3.2.- [ BRENDA ]   6.3.2.- [ KEGG ]   
PhosPhoSitePlusO60260
Domaine pattern : Prosite (Expaxy)UBIQUITIN_2 (PS50053)   
Domains : Interpro (EBI)E3_UB_ligase_RBR    IBR_dom    Parkin    Ubiquitin-rel_dom    Ubiquitin_dom   
Domain families : Pfam (Sanger)IBR (PF01485)    ubiquitin (PF00240)   
Domain families : Pfam (NCBI)pfam01485    pfam00240   
Domain families : Smart (EMBL)IBR (SM00647)  UBQ (SM00213)  
Conserved Domain (NCBI)PARK2
DMDM Disease mutations5071
Blocks (Seattle)PARK2
PDB (SRS)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
PDB (PDBSum)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
PDB (IMB)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
PDB (RSDB)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
Structural Biology KnowledgeBase1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
SCOP (Structural Classification of Proteins)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
CATH (Classification of proteins structures)1IYF    2JMO    4BM9    4I1F    4I1H    5C1Z    5C23    5C9V   
SuperfamilyO60260
Human Protein AtlasENSG00000185345
Peptide AtlasO60260
HPRD03967
IPIIPI00005254   IPI00332282   IPI00984693   IPI00470428   IPI00470429   IPI00332283   IPI00470427   
Protein Interaction databases
DIP (DOE-UCLA)O60260
IntAct (EBI)O60260
FunCoupENSG00000185345
BioGRIDPARK2
STRING (EMBL)PARK2
ZODIACPARK2
Ontologies - Pathways
QuickGOO60260
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  ubiquitin ligase complex  protein polyubiquitination  mitochondrial fission  mitophagy  mitophagy  mitophagy  transcription regulatory region sequence-specific DNA binding  G-protein coupled receptor binding  negative regulation of protein phosphorylation  startle response  transcription factor activity, sequence-specific DNA binding  actin binding  ubiquitin-protein transferase activity  ubiquitin-protein transferase activity  protein binding  nucleus  cytoplasm  mitochondrion  mitochondrion  mitochondrion  endoplasmic reticulum  Golgi apparatus  cytosol  cytosol  cytosol  transcription, DNA-templated  protein monoubiquitination  protein monoubiquitination  response to oxidative stress  mitochondrion organization  central nervous system development  learning  beta-catenin binding  zinc ion binding  adult locomotory behavior  proteasomal protein catabolic process  regulation of autophagy  positive regulation of gene expression  negative regulation of gene expression  positive regulation of mitochondrial fusion  negative regulation of mitochondrial fusion  regulation of mitochondrion organization  regulation of mitochondrion organization  regulation of mitochondrion organization  regulation of glucose metabolic process  free ubiquitin chain polymerization  regulation of dopamine secretion  tubulin binding  aggresome  macroautophagy  protein ubiquitination  protein ubiquitination  protein ubiquitination  ligase activity  SH3 domain binding  SCF ubiquitin ligase complex  enzyme binding  kinase binding  protein kinase binding  PDZ domain binding  Hsp70 protein binding  heat shock protein binding  regulation of protein ubiquitination  regulation of protein ubiquitination  ubiquitin conjugating enzyme binding  ubiquitin conjugating enzyme binding  ubiquitin protein ligase binding  protein destabilization  negative regulation of actin filament bundle assembly  regulation of lipid transport  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  negative regulation of glucokinase activity  cellular response to unfolded protein  response to endoplasmic reticulum stress  synaptic transmission, glutamatergic  protein K29-linked ubiquitination  ERAD pathway  regulation of dopamine metabolic process  norepinephrine metabolic process  dopamine metabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  identical protein binding  histone deacetylase binding  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of I-kappaB kinase/NF-kappaB signaling  ubiquitin binding  proteasome-mediated ubiquitin-dependent protein catabolic process  phospholipase binding  positive regulation of DNA binding  negative regulation of neuron apoptotic process  cellular protein catabolic process  cellular protein metabolic process  protein K27-linked ubiquitination  negative regulation by host of viral genome replication  positive regulation of protein catabolic process  positive regulation of transcription from RNA polymerase II promoter  negative regulation of JNK cascade  negative regulation of insulin secretion  perinuclear region of cytoplasm  protein stabilization  chaperone binding  positive regulation of neurotransmitter uptake  dopamine uptake involved in synaptic transmission  protein autoubiquitination  regulation of mitochondrial membrane potential  zinc ion homeostasis  negative regulation of cell death  regulation of canonical Wnt signaling pathway  ubiquitin protein ligase activity  ubiquitin protein ligase activity  neuron cellular homeostasis  protein K63-linked ubiquitination  protein K63-linked ubiquitination  protein K63-linked ubiquitination  protein localization to mitochondrion  aggresome assembly  protein K48-linked ubiquitination  protein K11-linked ubiquitination  cellular response to manganese ion  LUBAC complex  protein K6-linked ubiquitination  protein K6-linked ubiquitination  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of mitochondrial fission  negative regulation of release of cytochrome c from mitochondria  cellular response to toxic substance  Lewy body  cullin family protein binding  mitophagy in response to mitochondrial depolarization  mitophagy in response to mitochondrial depolarization  presynapse  regulation of cellular response to oxidative stress  regulation of cellular response to oxidative stress  negative regulation of neuron death  positive regulation of proteasomal protein catabolic process  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator  negative regulation of primary amine oxidase activity  positive regulation of protein linear polyubiquitination  regulation of synaptic vesicle transport  regulation of mitophagy  negative regulation of oxidative stress-induced cell death  negative regulation of oxidative stress-induced cell death  regulation of protein targeting to mitochondrion  positive regulation of tumor necrosis factor-mediated signaling pathway  cellular response to dopamine  negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of dendrite extension  negative regulation of spontaneous neurotransmitter secretion  ubiquitin protein ligase activity involved in ERAD pathway  ubiquitin-specific protease binding  F-box domain binding  Parkin-FBXW7-Cul1 ubiquitin ligase complex  regulation of reactive oxygen species metabolic process  negative regulation of reactive oxygen species metabolic process  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  ubiquitin ligase complex  protein polyubiquitination  mitochondrial fission  mitophagy  mitophagy  mitophagy  transcription regulatory region sequence-specific DNA binding  G-protein coupled receptor binding  negative regulation of protein phosphorylation  startle response  transcription factor activity, sequence-specific DNA binding  actin binding  ubiquitin-protein transferase activity  ubiquitin-protein transferase activity  protein binding  nucleus  cytoplasm  mitochondrion  mitochondrion  mitochondrion  endoplasmic reticulum  Golgi apparatus  cytosol  cytosol  cytosol  transcription, DNA-templated  protein monoubiquitination  protein monoubiquitination  response to oxidative stress  mitochondrion organization  central nervous system development  learning  beta-catenin binding  zinc ion binding  adult locomotory behavior  proteasomal protein catabolic process  regulation of autophagy  positive regulation of gene expression  negative regulation of gene expression  positive regulation of mitochondrial fusion  negative regulation of mitochondrial fusion  regulation of mitochondrion organization  regulation of mitochondrion organization  regulation of mitochondrion organization  regulation of glucose metabolic process  free ubiquitin chain polymerization  regulation of dopamine secretion  tubulin binding  aggresome  macroautophagy  protein ubiquitination  protein ubiquitination  protein ubiquitination  ligase activity  SH3 domain binding  SCF ubiquitin ligase complex  enzyme binding  kinase binding  protein kinase binding  PDZ domain binding  Hsp70 protein binding  heat shock protein binding  regulation of protein ubiquitination  regulation of protein ubiquitination  ubiquitin conjugating enzyme binding  ubiquitin conjugating enzyme binding  ubiquitin protein ligase binding  protein destabilization  negative regulation of actin filament bundle assembly  regulation of lipid transport  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  negative regulation of glucokinase activity  cellular response to unfolded protein  response to endoplasmic reticulum stress  synaptic transmission, glutamatergic  protein K29-linked ubiquitination  ERAD pathway  regulation of dopamine metabolic process  norepinephrine metabolic process  dopamine metabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  identical protein binding  histone deacetylase binding  neuron projection  positive regulation of I-kappaB kinase/NF-kappaB signaling  positive regulation of I-kappaB kinase/NF-kappaB signaling  ubiquitin binding  proteasome-mediated ubiquitin-dependent protein catabolic process  phospholipase binding  positive regulation of DNA binding  negative regulation of neuron apoptotic process  cellular protein catabolic process  cellular protein metabolic process  protein K27-linked ubiquitination  negative regulation by host of viral genome replication  positive regulation of protein catabolic process  positive regulation of transcription from RNA polymerase II promoter  negative regulation of JNK cascade  negative regulation of insulin secretion  perinuclear region of cytoplasm  protein stabilization  chaperone binding  positive regulation of neurotransmitter uptake  dopamine uptake involved in synaptic transmission  protein autoubiquitination  regulation of mitochondrial membrane potential  zinc ion homeostasis  negative regulation of cell death  regulation of canonical Wnt signaling pathway  ubiquitin protein ligase activity  ubiquitin protein ligase activity  neuron cellular homeostasis  protein K63-linked ubiquitination  protein K63-linked ubiquitination  protein K63-linked ubiquitination  protein localization to mitochondrion  aggresome assembly  protein K48-linked ubiquitination  protein K11-linked ubiquitination  cellular response to manganese ion  LUBAC complex  protein K6-linked ubiquitination  protein K6-linked ubiquitination  negative regulation of canonical Wnt signaling pathway  negative regulation of canonical Wnt signaling pathway  positive regulation of mitochondrial fission  negative regulation of release of cytochrome c from mitochondria  cellular response to toxic substance  Lewy body  cullin family protein binding  mitophagy in response to mitochondrial depolarization  mitophagy in response to mitochondrial depolarization  presynapse  regulation of cellular response to oxidative stress  regulation of cellular response to oxidative stress  negative regulation of neuron death  positive regulation of proteasomal protein catabolic process  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway  negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator  negative regulation of primary amine oxidase activity  positive regulation of protein linear polyubiquitination  regulation of synaptic vesicle transport  regulation of mitophagy  negative regulation of oxidative stress-induced cell death  negative regulation of oxidative stress-induced cell death  regulation of protein targeting to mitochondrion  positive regulation of tumor necrosis factor-mediated signaling pathway  cellular response to dopamine  negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway  negative regulation of endoplasmic reticulum stress-induced neuron intrinsic apoptotic signaling pathway  positive regulation of dendrite extension  negative regulation of spontaneous neurotransmitter secretion  ubiquitin protein ligase activity involved in ERAD pathway  ubiquitin-specific protease binding  F-box domain binding  Parkin-FBXW7-Cul1 ubiquitin ligase complex  regulation of reactive oxygen species metabolic process  negative regulation of reactive oxygen species metabolic process  
Pathways : KEGGUbiquitin mediated proteolysis    Protein processing in endoplasmic reticulum    Parkinson's disease   
REACTOMEO60260 [protein]
REACTOME PathwaysR-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation [pathway]
NDEx NetworkPARK2
Atlas of Cancer Signalling NetworkPARK2
Wikipedia pathwaysPARK2
Orthology - Evolution
OrthoDB5071
GeneTree (enSembl)ENSG00000185345
Phylogenetic Trees/Animal Genes : TreeFamPARK2
HOVERGENO60260
HOGENOMO60260
Homologs : HomoloGenePARK2
Homology/Alignments : Family Browser (UCSC)PARK2
Gene fusions - Rearrangements
Fusion : MitelmanARID1B/PARK2 [6q25.3/6q26]  [t(6;6)(q25;q26)]  
Fusion : MitelmanPARK2/STRADA [6q26/17q23.3]  [t(6;17)(q26;q23)]  
Fusion: TCGAARID1B 6q25.3 PARK2 6q26 LUAD
Fusion: TCGAPARK2 6q26 STRADA 17q23.3 LGG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPARK2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PARK2
dbVarPARK2
ClinVarPARK2
1000_GenomesPARK2 
Exome Variant ServerPARK2
ExAC (Exome Aggregation Consortium)PARK2 (select the gene name)
Genetic variants : HAPMAP5071
Genomic Variants (DGV)PARK2 [DGVbeta]
DECIPHER (Syndromes)6:161768590-163148834  ENSG00000185345
CONAN: Copy Number AnalysisPARK2 
Mutations
ICGC Data PortalPARK2 
TCGA Data PortalPARK2 
Broad Tumor PortalPARK2
OASIS PortalPARK2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPARK2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPARK2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)Parkinson's disease Mutation Database
LOVD (Leiden Open Variation Database)SpainMDB
BioMutasearch PARK2
DgiDB (Drug Gene Interaction Database)PARK2
DoCM (Curated mutations)PARK2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PARK2 (select a term)
intoGenPARK2
NCG5 (London)PARK2
Cancer3DPARK2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM167000    211980    600116    602544    607572   
Orphanet932   
MedgenPARK2
Genetic Testing Registry PARK2
NextProtO60260 [Medical]
TSGene5071
GENETestsPARK2
Huge Navigator PARK2 [HugePedia]
snp3D : Map Gene to Disease5071
BioCentury BCIQPARK2
ClinGenPARK2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5071
Chemical/Pharm GKB GenePA32942
Clinical trialPARK2
Miscellaneous
canSAR (ICR)PARK2 (select the gene name)
Other databaseGenomicus - Genomes in evolution
Other databasePhylomeDB 4
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePARK2
EVEXPARK2
GoPubMedPARK2
iHOPPARK2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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