Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Fabienne C. Fiesel
  • Thomas R. Caulfield
  • Owen A. Ross
  • Wolfdieter SpringerEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101588


Historical Background

Mutations in the PARKIN gene (chromosome 6q25–27) were first identified in 1998 as a cause for autosomal-recessive juvenile parkinsonism (AR-JP) (Kitada et al. 1998). By now hundreds of PARKIN mutations including single amino acid changes and deletions/duplications have been identified and account for more than 50% of cases with familial recessive Parkinson’s disease (PD) (Corti et al. 2011). In addition to their causative role in PD, mutations in PARKIN have also been found in numerous cancer tissues and a tumor suppressive role has been described for the protein (Xu et al. 2014). PARKINis located on chromosome 6 and is one of the largest genes in the human...

This is a preview of subscription content, log in to check access.


  1. Caulfield TR, Fiesel FC, Moussaud-Lamodiere EL, Dourado DF, Flores SC, Springer W. Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLoS Comput Biol. 2014;10:e1003935.  https://doi.org/10.1371/journal.pcbi.1003935.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev. 2011;91:1161–218.  https://doi.org/10.1152/physrev.00022.2010.CrossRefPubMedGoogle Scholar
  3. Durcan TM, Fon EA. The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications. Genes Dev. 2015;29:989–99.  https://doi.org/10.1101/gad.262758.115.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Feany MB, Pallanck LJ. Parkin: a multipurpose neuroprotective agent? Neuron. 2003;38:13–6.CrossRefPubMedGoogle Scholar
  5. Fiesel FC, Moussaud-Lamodiere EL, Ando M, Springer W. A specific subset of E2 ubiquitin-conjugating enzymes regulate Parkin activation and mitophagy differently. J Cell Sci. 2014;127:3488–504.  https://doi.org/10.1242/jcs.147520.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Fiesel FC, Ando M, Hudec R, Hill AR, Castanedes-Casey M, Caulfield TR, et al. (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO Rep. 2015a;16:1114–30.  https://doi.org/10.15252/embr.201540514.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fiesel FC, Caulfield TR, Moussaud-Lamodiere EL, Ogaki K, Dourado DF, Flores SC, et al. Structural and functional impact of Parkinson disease-associated mutations in the E3 ubiquitin ligase parkin. Hum Mutat. 2015b;36:774–86.  https://doi.org/10.1002/humu.22808.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010;12:119–31.  https://doi.org/10.1038/ncb2012.CrossRefPubMedGoogle Scholar
  9. Greene JC, Whitworth AJ, Kuo I, Andrews LA, Feany MB, Pallanck LJ. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA. 2003;100:4078–83.  https://doi.org/10.1073/pnas.0737556100.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Kahle PJ, Haass C. How does parkin ligate ubiquitin to Parkinson’s disease? EMBO Rep. 2004;5:681–5.  https://doi.org/10.1038/sj.embor.7400188.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.  https://doi.org/10.1038/33416.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803.  https://doi.org/10.1083/jcb.200809125.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Pallanck L, Greenamyre JT. Neurodegenerative disease: pink, parkin and the brain. Nature. 2006;441:1058.  https://doi.org/10.1038/4411058a.CrossRefPubMedGoogle Scholar
  14. Roberts RF, Tang MY, Fon EA, Durcan TM. Defending the mitochondria: the pathways of mitophagy and mitochondrial-derived vesicles. Int J Biochem Cell Biol. 2016;  https://doi.org/10.1016/j.biocel.2016.07.020.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, et al. Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature. 2013;496:372–6.  https://doi.org/10.1038/nature12043.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25:302–5.  https://doi.org/10.1038/77060.CrossRefPubMedGoogle Scholar
  17. Springer W, Kahle PJ. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy. 2011;7:266–78.PubMedCrossRefGoogle Scholar
  18. Walden H, Martinez-Torres RJ. Regulation of Parkin E3 ubiquitin ligase activity. Cell Mol Life Sci. 2012;69:3053–67.  https://doi.org/10.1007/s00018-012-0978-5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Wenzel DM, Lissounov A, Brzovic PS, Klevit RE. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature. 2011;474:105–8.  https://doi.org/10.1038/nature09966.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Xu L, Lin DC, Yin D, Koeffler HP. An emerging role of PARK2 in cancer. J Mol Med (Berl). 2014;92:31–42.  https://doi.org/10.1007/s00109-013-1107-0.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Fabienne C. Fiesel
    • 1
  • Thomas R. Caulfield
    • 1
  • Owen A. Ross
    • 1
  • Wolfdieter Springer
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo Clinic, Mayo Clinic Graduate School of Biomedical SciencesJacksonvilleUSA