sequestosome-1; phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kD; ubiquitin-binding protein p62; EBI3-associated protein of 60 kD; p60; EBIAP (SQSTM1, ORCA, OSIL)
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Function
- role in protein degradation
- adapter protein
- binds ubiquitin, polyubiquitin-binding protein
- degraded by autophagy
- autophagy suppresses tumorigenesis through elimination of SQSTM1[4]
- interacts with autophagic effector proteins LC3A & LC3B[1] & the related gamma-aminobutyrate receptor-associated protein
- role in activation of transcription factor NF-kappa B
- linked to extrinsic apoptosis pathway
- activation of NFKB1 by TNF-alpha, NGF, IL1
- titin downstream signaling in muscle cells
- regulation of signaling cascades via ubiquitination
- cell differentiation, apoptosis, immune response, regulation of K+ channels
- interactions: PRKCI, PRKCZ, KCNAB1, GABRR1, GABRR2, GABRR3, EBI3, LCK, RASA1, PRKCZ, PRKCI, NR2F2, NTRK1,NTRK2, NTRK3, NBR1, MAP2K5, TRIM55, MAPKAPK5, PSMD4, PSMC2, RIPK1 K63-polyubiquitinated MAPT
- forms ternary complexes with PRKCZ &KCNAB2 or PRKCZ & GABBR3
- forms an NGF-induced complex with IKBKB, PRKCI, TRAF6
- forms a complex with MAP2K5 & PRKCZ or PRKCI
- forms complex with JUB, PRKCZ & TRAF6
- forms ternary complex with PAWR & PRKCZ
- phosphorylated by PRKCZ, TTN
Structure
- homooligomer or heterooligomer
- UBA domain binds specifically Lys-63-linked polyubiquitin chains of polyubiquitinated substrates & mediates the interaction with TRIM55
- OPR domain mediates homooligomerization & interactions with PRKCZ, PRKCI, MAP2K5, NBR1
- ZZ-type zinc finger mediates interaction with RIPK1
Compartment
- cytoplasm
- in cardiac muscles localizes to sarcomeric band
- localizes to late endosomes
- may also localize to the nucleus
Expression
- induction by proteasomal inhibitor PSI, prostaglandin J2, phorbol 12-myristate 13-acetate
Pathology
- defects in SQSTM1 are a cause of Paget's disease of bone
- accumulates in neurofibrillary tangles & in Lewy bodies of neurons from patients with Alzheimer's & Parkinson's disease, respectively
- found in Rosenthal fibers of pilocytic astrocytoma
- accumulates in Mallory bodies
- accumulates in hyaline bodies associated with hepatocellular carcinoma
More general terms
References
- ↑ 1.0 1.1 UniProt http://www.uniprot.org/uniprot/Q13501.html
- ↑ Pankiv S et al p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy J. Biol. Chem. 2007, 282:24131-2414 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17580304
- ↑ Ichimura Y Selective turnover of p62/A170/SQSTM1 by autophagy Autophagy. 2008 Nov 16;4(8):1063-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18776737
- ↑ 4.0 4.1 Komatsu M et al Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient Mice Cell 2007, 131:1149-1163 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18083104
- ↑ Mathew R et al Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009, 137(6):1062-75 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19524509
Moscat J et al p62 at the Crossroads of Autophagy, Apoptosis, and Cancer Cell 2009, 137:1001-1004 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19524504