P62 at the Crossroads of Autophagy, Apoptosis, and Cancer

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2009 Jun 16

PMID 19524504

Citations 572

Authors

Jorge Moscat

Maria T Diaz-Meco

Affiliations

Soon will be listed here.

Abstract

The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-kappaB. Recent findings link p62 activity to the extrinsic apoptosis pathway, and Mathew et al. (2009) now show that the modulation of p62 by autophagy is a key factor in tumorigenesis. These findings place p62 at critical decision points that control cell death and survival.

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References

Kirkin V, Lamark T, Sou Y, Bjorkoy G, Nunn J, Bruun J . A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009; 33(4):505-16. DOI: 10.1016/j.molcel.2009.01.020. View

Kim P, Hailey D, Mullen R, Lippincott-Schwartz J . Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci U S A. 2008; 105(52):20567-74. PMC: 2602605. DOI: 10.1073/pnas.0810611105. View

Korolchuk V, Mansilla A, Menzies F, Rubinsztein D . Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell. 2009; 33(4):517-27. PMC: 2669153. DOI: 10.1016/j.molcel.2009.01.021. View

Hiruma Y, Kurihara N, Subler M, Zhou H, Boykin C, Zhang H . A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment. Hum Mol Genet. 2008; 17(23):3708-19. PMC: 2581430. DOI: 10.1093/hmg/ddn266. View

Duran A, Linares J, Galvez A, Wikenheiser K, Flores J, Diaz-Meco M . The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis. Cancer Cell. 2008; 13(4):343-54. DOI: 10.1016/j.ccr.2008.02.001. View

Moscat J, Diaz-Meco M, Wooten M . Signal integration and diversification through the p62 scaffold protein. Trends Biochem Sci. 2006; 32(2):95-100. DOI: 10.1016/j.tibs.2006.12.002. View

Duran A, Serrano M, Leitges M, Flores J, Picard S, Brown J . The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis. Dev Cell. 2004; 6(2):303-9. DOI: 10.1016/s1534-5807(03)00403-9. View

Sanz L, Diaz-Meco M, Nakano H, Moscat J . The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J. 2000; 19(7):1576-86. PMC: 310227. DOI: 10.1093/emboj/19.7.1576. View

Pankiv S, Clausen T, Lamark T, Brech A, Bruun J, Outzen H . p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007; 282(33):24131-45. DOI: 10.1074/jbc.M702824200. View

10.

Jin Z, Li Y, Pitti R, Lawrence D, Pham V, Lill J . Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell. 2009; 137(4):721-35. DOI: 10.1016/j.cell.2009.03.015. View

11.

Nezis I, Simonsen A, Sagona A, Finley K, Gaumer S, Contamine D . Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain. J Cell Biol. 2008; 180(6):1065-71. PMC: 2290837. DOI: 10.1083/jcb.200711108. View

12.

Laurin N, Brown J, Morissette J, Raymond V . Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002; 70(6):1582-8. PMC: 379146. DOI: 10.1086/340731. View

13.

Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T . Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007; 131(6):1149-63. DOI: 10.1016/j.cell.2007.10.035. View

14.

Zatloukal K, Stumptner C, Fuchsbichler A, Heid H, Schnoelzer M, Kenner L . p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol. 2002; 160(1):255-63. PMC: 1867135. DOI: 10.1016/S0002-9440(10)64369-6. View

15.

Kurihara N, Hiruma Y, Zhou H, Subler M, Dempster D, Singer F . Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J Clin Invest. 2006; 117(1):133-42. PMC: 1705822. DOI: 10.1172/JCI28267. View

16.

Mathew R, Kongara S, Beaudoin B, Karp C, Bray K, Degenhardt K . Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007; 21(11):1367-81. PMC: 1877749. DOI: 10.1101/gad.1545107. View

17.

Geetha T, Jiang J, Wooten M . Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell. 2005; 20(2):301-12. DOI: 10.1016/j.molcel.2005.09.014. View

18.

Moscat J, Diaz-Meco M, Albert A, Campuzano S . Cell signaling and function organized by PB1 domain interactions. Mol Cell. 2006; 23(5):631-40. DOI: 10.1016/j.molcel.2006.08.002. View

19.

Rodriguez A, Duran A, Selloum M, Champy M, Diez-Guerra F, Maria Flores J . Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metab. 2006; 3(3):211-22. DOI: 10.1016/j.cmet.2006.01.011. View

20.

Mathew R, Karp C, Beaudoin B, Vuong N, Chen G, Chen H . Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009; 137(6):1062-75. PMC: 2802318. DOI: 10.1016/j.cell.2009.03.048. View