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{{other uses|Parkin (disambiguation)}}
{{Infobox_gene}}
'''Parkin''' is a 465-[[amino acid]] [[residue (chemistry)|residue]] [[E3 ubiquitin ligase]], a [[protein]] that in humans and mice is encoded by the ''PARK2'' [[gene]].<ref name="pmid9560156">{{cite journal | vauthors = Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N | title = Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism | journal = Nature | volume = 392 | issue = 6676 | pages = 605–8 | date = April 1998 | pmid = 9560156 | doi = 10.1038/33416 | bibcode = 1998Natur.392..605K | s2cid = 4432261 }}</ref><ref name="pmid9570960">{{cite journal | vauthors = Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y | title = A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2) | journal = Genomics | volume = 49 | issue = 1 | pages = 143–6 | date = April 1998 | pmid = 9570960 | doi = 10.1006/geno.1997.5196 }}</ref> Parkin plays a critical role in [[ubiquitination]] – the process whereby molecules are covalently labelled with [[ubiquitin]] (Ub) and directed towards degradation in [[proteasomes]] or [[lysosomes]]. Ubiquitination involves the sequential action of three enzymes. First, an [[E1 ubiquitin-activating enzyme]] binds to inactive Ub in [[eukaryotic cells]] via a [[thioester]] bond and mobilises it in an ATP-dependent process. Ub is then transferred to an [[E2 ubiquitin-conjugating enzyme]] before being conjugated to the target protein via an E3 ubiquitin ligase.<ref name="Pickart and Eddins 2004">{{cite journal | vauthors = Pickart CM, Eddins MJ | title = Ubiquitin: structures, functions, mechanisms | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1695 | issue = 1–3 | pages = 55–72 | date = November 2004 | pmid = 15571809 | doi = 10.1016/j.bbamcr.2004.09.019 | doi-access = free }}</ref> There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
In particular, parkin recognises proteins on the outer membrane of [[mitochondria]] upon cellular insult and mediates the clearance of damaged mitochondria via [[autophagy]] and proteasomal mechanisms.<ref name="Seirafi_2015">{{cite journal | vauthors = Seirafi M, Kozlov G, Gehring K | title = Parkin structure and function | journal = The FEBS Journal | volume = 282 | issue = 11 | pages = 2076–88 | date = June 2015 | pmid = 25712550 | pmc = 4672691 | doi = 10.1111/febs.13249 }}</ref> Parkin also enhances cell survival by suppressing both mitochondria-dependent and -independent [[apoptosis]]. [[Mutations]] are associated with mitochondrial dysfunction, leading to neuronal death in [[
==Structure==
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of 8 Zn2+/parkin.]]
Like other members of the RING-between-RING (RBR) family of E3 ligases, parkin possesses two [[RING finger domain]]s and an in-between-RING (IBR) region. [[RING1]] forms the binding site for E2 Ub-conjugating enzyme while RING2 contains the catalytic [[cysteine]] residue (Cys431) that cleaves Ub off E2 and transiently binds it to E3 via a thioester bond.<ref name="Seirafi_2015" /> Ub transfer is aided by neighbouring residues [[histidine]] His433, which accepts a proton from Cys431 to activate it, and [[glutamate]] Glu444, which is involved in autoubiquitination.<ref name="Trempe 2013">{{cite journal | vauthors = Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY, Ménade M, Al-Abdul-Wahid S, Krett J, Wong K, Kozlov G, Nagar B, Fon EA, Gehring K | title = Structure of parkin reveals mechanisms for ubiquitin ligase activation | journal = Science | volume = 340 | issue = 6139 | pages = 1451–5 | date = June 2013 | pmid = 23661642 | doi = 10.1126/science.1237908 | bibcode = 2013Sci...340.1451T | s2cid = 206548928 | doi-access = free }}</ref> Together these form the [[catalytic triad]], whose assembly is required for parkin activation.<ref name="Riley 2013">{{cite journal | vauthors = Riley BE, Lougheed JC, Callaway K, Velasquez M, Brecht E, Nguyen L, Shaler T, Walker D, Yang Y, Regnstrom K, Diep L, Zhang Z, Chiou S, Bova M, Artis DR, Yao N, Baker J, Yednock T, Johnston JA | title = Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases | journal = Nature Communications | volume = 4 | pages = 1982 | date = 2013 | pmid = 23770887 | doi = 10.1038/ncomms2982 | pmc=3709503| bibcode = 2013NatCo...4.1982R }}</ref> Parkin also contains an [[N-terminal]] Ub-like domain (Ubl) for specific [[substrate (biochemistry)|substrate]] recognition, a unique RING0 domain and a repressor (REP) region that tonically suppresses ligase activity.
Under resting conditions, the tightly coiled conformation of parkin renders it inactive, as access to the catalytic RING2 residue is [[steric]]ally blocked by RING0, while the E2 binding domain on RING1 is occluded by Ubl and REP.<ref name="Seirafi_2015" /> Activating stimuli disrupt these interdomain interactions and induce parkin to collapse along the RING1-RING0 interface.<ref name="Riley 2013" /> The active site of RING2 is drawn towards E2-Ub bound to RING1, facilitating formation of the Ub-thioester intermediate. Parkin activation requires [[phosphorylation]] of [[serine]] Ser65 in Ubl by [[serine/threonine kinase]], [[PINK1]]. Addition of a charged [[phosphate]] destabilises [[hydrophobic interactions]] between Ubl and neighbouring subregions, reducing autoinhibitory effects of this N-terminus domain.<ref name="Koyano 2014">{{cite journal | vauthors = Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M, Kimura Y, Tsuchiya H, Yoshihara H, Hirokawa T, Endo T, Fon EA, Trempe JF, Saeki Y, Tanaka K, Matsuda N | title = Ubiquitin is phosphorylated by PINK1 to activate parkin | journal = Nature | volume = 510 | issue = 7503 | pages = 162–6 | date = June 2014 | pmid = 24784582 | doi = 10.1038/nature13392 | bibcode = 2014Natur.510..162K | s2cid = 4390259 }}</ref> Ser65Ala [[missense mutation]]s were found to ablate Ub-parkin binding whilst inhibiting parkin recruitment to damaged mitochondria.<ref name="Iguchi 2013">{{cite journal | vauthors = Iguchi M, Kujuro Y, Okatsu K, Koyano F, Kosako H, Kimura M, Suzuki N, Uchiyama S, Tanaka K, Matsuda N | title = Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation | journal = The Journal of Biological Chemistry | volume = 288 | issue = 30 | pages = 22019–32 | date = July 2013 | pmid = 23754282 | doi = 10.1074/jbc.M113.467530 | pmc=3724655| doi-access = free }}</ref> PINK1 also phosphorylates Ub at Ser65, accelerating its discharge from E2 and enhancing its [[Chemical affinity|affinity]] for parkin.<ref name="Koyano 2014" />
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Although structural changes following phosphorylation are uncertain, [[crystallisation]] of parkin revealed a cationic pocket in RING0 formed by [[lysine]] and [[arginine]] residues Lys161, Arg163 and Lys211 that forms a putative phosphate binding site.<ref name="Wauer and Komander 2013">{{cite journal | vauthors = Wauer T, Komander D | title = Structure of the human Parkin ligase domain in an autoinhibited state | journal = The EMBO Journal | volume = 32 | issue = 15 | pages = 2099–112 | date = July 2013 | pmid = 23727886 | doi = 10.1038/emboj.2013.125 | pmc=3730226}}</ref> Considering that RING0 is unique to parkin and that its hydrophobic interface with RING1 buries Cys431 in inactive parkin,<ref name= "Iguchi 2013" /> targeting of phosphorylated Ub and/or Ubl towards this binding niche might be critical in dismantling autoinhibitory complexes during parkin activation.
==
===Mitophagy===
Parkin plays a crucial role in [[mitophagy]] and clearance of [[reactive oxygen species]].<ref name="Olszewska 2015">{{cite journal | doi=10.3389/fneur.2015.00035| pmid=25759682| pmc=4338761| title=Will Crystal Parkin Help in Understanding the Future of
Parkin substrates include mitofusins Mfn1 and Mfn2, which are large [[GTPase]]s that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of [[oxidative phosphorylation]].<ref name="Youle and van der Bliek 2012">{{cite journal | vauthors = Youle RJ, van der Bliek AM | title = Mitochondrial fission, fusion, and stress | journal = Science | volume = 337 | issue = 6098 | pages = 1062–5 | date = August 2012 | pmid = 22936770 | doi = 10.1126/science.1219855 | pmc=4762028| bibcode = 2012Sci...337.1062Y }}</ref> However, upon mitochondrial damage, degradation of fusion proteins is necessary to separate them from the network via [[mitochondrial fission]] and prevent the corruption of healthy mitochondria.<ref name="Twig 2008">{{cite journal | vauthors = Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS | title = Fission and selective fusion govern mitochondrial segregation and elimination by autophagy | journal = The EMBO Journal | volume = 27 | issue = 2 | pages = 433–46 | date = January 2008 | pmid = 18200046 | doi = 10.1038/sj.emboj.7601963 | pmc=2234339}}</ref> Parkin is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation. [[Proteomic]] studies identified additional OMM proteins as parkin substrates, including fission protein FIS, its adaptor [[TBC1D15]] and [[translocase]] [[TOMM20]] and TOMM70 that facilitate movement of proteins such as PINK1 across OMM.<ref name="Sarraf 2013">{{cite journal | vauthors = Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW | title = Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization | journal = Nature | volume = 496 | issue = 7445 | pages = 372–6 | date = April 2013 | pmid = 23503661 | doi = 10.1038/nature12043 | pmc=3641819| bibcode = 2013Natur.496..372S }}</ref> [[Miro (protein)|Miro]] (or [[RHOT1]]/[[RHOT2]]) is an OMM protein critical for [[axonal transport]], and may be ubiquitinated and targeted towards proteasomal degradation by parkin.<ref name= "Narendra 2012">{{cite journal | vauthors = Narendra D, Walker JE, Youle R | title = Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 11 | pages = a011338 | date = November 2012 | pmid = 23125018 | doi = 10.1101/cshperspect.a011338 | pmc=3536340}}</ref> Miro breakdown produced a marked decrease in migration of compromised mitochondria along [[axons]] of mouse [[hippocampal]] [[neurons]],<ref name="Shlevkov 2016">{{cite journal | vauthors = Shlevkov E, Kramer T, Schapansky J, LaVoie MJ, Schwarz TL | title = Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 41 | pages = E6097–E6106 | date = October 2016 | pmid = 27679849 | doi = 10.1073/pnas.1612283113 | pmc=5068282| bibcode = 2016PNAS..113E6097S | doi-access = free }}</ref> reinforcing the importance of parkin in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy.▼
▲Parkin plays a crucial role in [[mitophagy]] and clearance of [[reactive oxygen species]].<ref name="Olszewska 2015">{{cite journal | doi=10.3389/fneur.2015.00035| pmid=25759682| pmc=4338761| title=Will Crystal Parkin Help in Understanding the Future of Parkinson’s Disease?| journal=Frontiers in Neurology| volume=6| pages=35| year=2015| last1=Olszewska| first1=Diana Angelika| last2=Lynch| first2=Tim| doi-access=free}}</ref> Mitophagy is the elimination of damaged mitochondria in [[autophagosomes]], and is dependent on a [[positive feedback]] cycle involving synergistic action of parkin and PINK1. Following severe cellular insult, rundown of mitochondrial [[membrane potential]] prevents import of PINK1 into the [[mitochondrial matrix]] and causes it to aggregate on the outer mitochondrial membrane (OMM).<ref name="Durcan 2015">{{cite journal | vauthors = Durcan TM, Fon EA | title = The three 'P's of mitophagy: PARKIN, PINK1, and post-translational modifications | journal = Genes & Development | volume = 29 | issue = 10 | pages = 989–99 | date = May 2015 | pmid = 25995186 | doi = 10.1101/gad.262758.115 | pmc=4441056}}</ref> Parkin is recruited to mitochondria following [[depolarisation]] and phosphorylated by PINK1, which simultaneously phosphorylates Ub pre-conjugated to mitochondrial membrane proteins. PINK1 and Ub phosphorylation facilitate parkin activation and further assembly of mono- and poly-Ub chains.<ref name="Koyano 2014" /> Considering the proximity of these chains to PINK1, further phosphorylation of Ub at Ser65 is likely, potentiating parkin mobilisation and substrate ubiquitination in a [[self-reinforcing cycle]].<ref name="Seirafi_2015" />
▲Parkin substrates include mitofusins Mfn1 and Mfn2, which are large [[GTPase]]s that promote mitochondria fusion into dynamic, tubular complexes that maximise efficiency of [[oxidative phosphorylation]].<ref name="Youle and van der Bliek 2012">{{cite journal | vauthors = Youle RJ, van der Bliek AM | title = Mitochondrial fission, fusion, and stress | journal = Science | volume = 337 | issue = 6098 | pages = 1062–5 | date = August 2012 | pmid = 22936770 | doi = 10.1126/science.1219855 | pmc=4762028| bibcode = 2012Sci...337.1062Y }}</ref> However, upon mitochondrial damage, degradation of fusion proteins is necessary to separate them from the network via [[mitochondrial fission]] and prevent the corruption of healthy mitochondria.<ref name="Twig 2008">{{cite journal | vauthors = Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS | title = Fission and selective fusion govern mitochondrial segregation and elimination by autophagy | journal = The EMBO Journal | volume = 27 | issue = 2 | pages = 433–46 | date = January 2008 | pmid = 18200046 | doi = 10.1038/sj.emboj.7601963 | pmc=2234339}}</ref> Parkin is therefore required before mitophagy as it ubiquinates Mfn1/2, labelling it for proteasomal degradation. [[Proteomic]] studies identified additional OMM proteins as parkin substrates, including fission protein FIS, its adaptor [[TBC1D15]] and [[translocase]] [[TOMM20]] and TOMM70 that facilitate movement of proteins such as PINK1 across OMM.<ref name="Sarraf 2013">{{cite journal | vauthors = Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW | title = Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization | journal = Nature | volume = 496 | issue = 7445 | pages = 372–6 | date = April 2013 | pmid = 23503661 | doi = 10.1038/nature12043 | pmc=3641819| bibcode = 2013Natur.496..372S }}</ref> [[Miro (protein)|Miro]] (or [[RHOT1]]/[[RHOT2]]) is an OMM protein critical for [[axonal transport]], and may be ubiquitinated and targeted towards proteasomal degradation by parkin.<ref name= "Narendra 2012">{{cite journal | vauthors = Narendra D, Walker JE, Youle R | title = Mitochondrial quality control mediated by PINK1 and Parkin: links to parkinsonism | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 11 | pages = a011338 | date = November 2012 | pmid = 23125018 | doi = 10.1101/cshperspect.a011338 | pmc=3536340}}</ref> Miro breakdown produced a marked decrease in migration of compromised mitochondria along [[axons]] of mouse [[hippocampal]] [[neurons]],<ref name="Shlevkov 2016">{{cite journal | vauthors = Shlevkov E, Kramer T, Schapansky J, LaVoie MJ, Schwarz TL | title = Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 41 | pages = E6097–E6106 | date = October 2016 | pmid = 27679849 | doi = 10.1073/pnas.1612283113 | pmc=5068282| doi-access = free }}</ref> reinforcing the importance of parkin in segregating defective mitochondria from their functioning counterparts and limiting the spatial spread of mitochondrial dysfunction, prior to autophagy.
During mitophagy, parkin targets [[VDAC1]], a voltage-gated anion channel that undergoes a conformational change upon mitochondrial membrane depolarisation, exposing a [[cytosolic]] domain for ubiquitination.<ref name="Durcan 2015" /> Silencing of VDAC1 expression in [[HeLa]] cells significantly reduced parkin recruitment to depolarised mitochondria and their subsequent clearance,<ref name="Geisler 2010">{{cite journal | vauthors = Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W | title = PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1 | journal = Nature Cell Biology | volume = 12 | issue = 2 | pages = 119–31 | date = February 2010 | pmid = 20098416 | doi = 10.1038/ncb2012 | s2cid = 26096413 }}</ref> highlighting the critical role of VDAC1 as a selective marker of mitochondrial damage and instigator of mitophagy. Following Ub conjugation, parkin recruits autophagy receptors such as p62, [[TAX1BP1]] and [[CALCOCO2]], facilitating assembly of autophagosomes that digest defective mitochondria.<ref name="Sarraf 2013" />
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==Clinical significance==
===
'''PARK2''' ([[OMIM]] [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602544 *602544]) is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease ([[OMIM]] [https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600116 600116]) due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset [[Parkinson disease]]. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% [[homozygous]] mutations.<ref name="pmid15266615">{{cite journal | vauthors = Poorkaj P, Nutt JG, James D, Gancher S, Bird TD, Steinbart E, Schellenberg GD, Payami H | title = parkin mutation analysis in clinic patients with early-onset Parkinson [corrected] disease | journal = American Journal of Medical Genetics. Part A | volume = 129A | issue = 1 | pages = 44–50 | date = August 2004 | pmid = 15266615 | doi = 10.1002/ajmg.a.30157 | s2cid = 85058092 | url = https://zenodo.org/record/1229109 }}</ref> Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).<ref name="pmid12891670">{{cite journal | vauthors = Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destée A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A | title = How much phenotypic variation can be attributed to parkin genotype? | journal = Annals of Neurology | volume = 54 | issue = 2 | pages = 176–85 | date = August 2003 | pmid = 12891670 | doi = 10.1002/ana.10613 | s2cid = 6411438 }}</ref>
Patients with parkin mutations (PARK2) do not have [[Lewy body|Lewy bodies]]. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
In humans, [[loss-of-function]] mutations in parkin ''[[PARK2]]'' gene have been implicated in 50% of inherited and 15% of juvenile-onset [[Sporadic disease|sporadic]] forms of [[
While mitochondria are essential for ATP generation in any [[eukaryotic cell]], [[catecholaminergic]] neurons are particularly reliant on their proper function for clearance of reactive oxygen species produced by dopamine metabolism, and to supply high energy requirements of catecholamine synthesis.<ref name="Durcan 2015" /> Their susceptibility to oxidative damage and metabolic stress render catecholaminergic neurons vulnerable to [[neurotoxicity]] associated with aberrant regulation of mitochondrial activity, as is postulated to occur in both inherited and idiopathic PD. For example, enhanced oxidative stress in neurons, [[skeletal muscle]] and [[platelets]], corresponding with reduced activity of [[complex I]] in the [[electron transport chain]] were reported in PD patients,<ref name="Keeney 2006">{{cite journal | vauthors = Keeney PM, Xie J, Capaldi RA, Bennett JP | title = Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled | journal = The Journal of Neuroscience | volume = 26 | issue = 19 | pages = 5256–64 | date = May 2006 | pmid = 16687518 | pmc = 6674236 | doi = 10.1523/JNEUROSCI.0984-06.2006 }}</ref> while deletions in the [[mitochondrial genome]] were found in the SNpc.<ref name="Bender 2006">{{cite journal | vauthors = Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM | title = High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 515–7 | date = May 2006 | pmid = 16604074 | doi = 10.1038/ng1769 | s2cid = 13956928 }}</ref>
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===Tumourigenesis===
Consistent with
▲Consistent with parkin’s potent anti-tumourigenic abilities, negative mutations and deletions have been reported in various tumours. For example, ''PARK2'' [[copy number]] was reduced in 85% of [[glioblastoma]] samples while [[lung cancer]]s were associated with [[heterozygous]] deletion of ''PARK2'' at 6q25-q27 locus.<ref name="Veeriah 2010">{{cite journal|author-link16=Paul Mischel|author-link18=Timothy Cloughesy | vauthors = 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 | title = Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies | journal = Nature Genetics | volume = 42 | issue = 1 | pages = 77–82 | date = January 2010 | pmid = 19946270 | doi = 10.1038/ng.491 | pmc=4002225}}</ref> Parkin deficiency further diminished disease-free survival in infrared-irradiated mice without increasing tumour [[incidence rate]], suggesting that parkin deficiencies increase susceptibility to tumour-promoting events, rather than initiating tumour formation.<ref name="Zhang 2011" /> Similarly, chromosomal breaks in ''PARK2'' suppressed expression of [[afadin]] [[scaffold protein]] in [[breast cancer]], thereby comprising [[epithelial]] integrity, enhancing [[metastatic]] potential and worsening overall [[prognosis]].<ref name="Letessier 2007">{{cite journal | vauthors = Letessier A, Garrido-Urbani S, Ginestier C, Fournier G, Esterni B, Monville F, Adélaïde J, Geneix J, Xerri L, Dubreuil P, Viens P, Charafe-Jauffret E, Jacquemier J, Birnbaum D, Lopez M, Chaffanet M | title = Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer | journal = Oncogene | volume = 26 | issue = 2 | pages = 298–307 | date = January 2007 | pmid = 16819513 | doi = 10.1038/sj.onc.1209772 | doi-access = free }}</ref> [[Haploinsufficient]] ''PARK2'' expression, either due to reduced copy number or DNA [[hypermethylation]], was further detected in spontaneous [[colorectal cancer]] where it accelerated all stages of intestinal [[adenoma]] development in mouse models.<ref name="Poulogiannis 2010">{{cite journal | vauthors = Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, Arends MJ | title = PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 34 | pages = 15145–50 | date = August 2010 | pmid = 20696900 | doi = 10.1073/pnas.1009941107 | pmc=2930574| bibcode = 2010PNAS..10715145P | doi-access = free }}</ref> Parkin is therefore a potent modulator of tumour progression, without directly instigating tumourigenesis.
▲== Interactions ==
▲Parkin (ligase) has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Alpha-synuclein]],<ref name = pmid11588587>{{cite journal | vauthors = Choi P, Golts N, Snyder H, Chong M, Petrucelli L, Hardy J, Sparkman D, Cochran E, Lee JM, Wolozin B | title = Co-association of parkin and alpha-synuclein | journal = NeuroReport | volume = 12 | issue = 13 | pages = 2839–43 | date = September 2001 | pmid = 11588587 | doi = 10.1097/00001756-200109170-00017 | s2cid = 83941655 | author10-link = Benjamin Wolozin }}</ref><ref name = pmid18195004>{{cite journal | vauthors = Kawahara K, Hashimoto M, Bar-On P, Ho GJ, Crews L, Mizuno H, Rockenstein E, Imam SZ, Masliah E | title = alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease | journal = The Journal of Biological Chemistry | volume = 283 | issue = 11 | pages = 6979–87 | date = March 2008 | pmid = 18195004 | doi = 10.1074/jbc.M710418200 | doi-access = free }}</ref>
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{{Reflist|33em}}
==
{{refbegin|33em}}
* {{cite journal | vauthors = Saito M, Matsumine H, Tanaka H, Ishikawa A, Matsubayashi S, Hattori Y, Mizuno Y, Tsuji S | title = [Clinical characteristics and linkage analysis of autosomal recessive form of juvenile parkinsonism(AR-JP)] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 55 | issue = 1 | pages = 83–8 | date = January 1997 | pmid = 9014427 }}
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* {{cite journal | vauthors = Pankratz N, Foroud T | title = Genetics of Parkinson disease | journal = NeuroRx | volume = 1 | issue = 2 | pages = 235–42 | date = April 2004 | pmid = 15717024 | pmc = 534935 | doi = 10.1602/neurorx.1.2.235 }}
* {{cite journal | vauthors = Suzuki H | title = Protein-protein interactions in the mammalian brain | journal = The Journal of Physiology | volume = 575 | issue = Pt 2 | pages = 373–7 | date = September 2006 | pmid = 16840513 | pmc = 1819454 | doi = 10.1113/jphysiol.2006.115717 }}
* {{cite
* {{cite journal | vauthors = Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schäffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y | title = Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27 | journal = American Journal of Human Genetics | volume = 60 | issue = 3 | pages = 588–96 | date = March 1997 | pmid = 9042918 | pmc = 1712507 }}
* {{cite journal | vauthors = Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N | title = Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism | journal = Nature | volume = 392 | issue = 6676 | pages = 605–8 | date = April 1998 | pmid = 9560156 | doi = 10.1038/33416 | bibcode = 1998Natur.392..605K | s2cid = 4432261 }}
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* {{cite journal | vauthors = Abbas N, Lücking CB, Ricard S, Dürr A, Bonifati V, De Michele G, Bouley S, Vaughan JR, Gasser T, Marconi R, Broussolle E, Brefel-Courbon C, Harhangi BS, Oostra BA, Fabrizio E, Böhme GA, Pradier L, Wood NW, Filla A, Meco G, Denefle P, Agid Y, Brice A | title = A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease | journal = Human Molecular Genetics | volume = 8 | issue = 4 | pages = 567–74 | date = April 1999 | pmid = 10072423 | doi = 10.1093/hmg/8.4.567 | doi-access = free }}
* {{cite journal | vauthors = Sunada Y, Saito F, Matsumura K, Shimizu T | title = Differential expression of the parkin gene in the human brain and peripheral leukocytes | journal = Neuroscience Letters | volume = 254 | issue = 3 | pages = 180–2 | date = October 1998 | pmid = 10214987 | doi = 10.1016/S0304-3940(98)00697-1 | s2cid = 32794960 }}
* {{cite journal | vauthors = Shimura H, Hattori N, Kubo S, Yoshikawa M, Kitada T, Matsumine H, Asakawa S, Minoshima S, Yamamura Y, Shimizu N, Mizuno Y | title = Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients | journal = Annals of Neurology | volume = 45 | issue = 5 | pages = 668–72 | date = May 1999 | pmid = 10319893 | doi = 10.1002/1531-8249(199905)45:5<668::AID-ANA19>3.0.CO;2-Z | s2cid = 37299782 }}
{{refend}}
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* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=jpd GeneReviews/NCBI/NIH/UW entry on Parkin Type of Juvenile Parkinson Disease]
* {{MeshName|parkin+protein}}
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