Disease relevance of SQSTM1

• These studies confirm that mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget's disease of bone [1].
• Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies [2].
• p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells [3].
• New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Paget's disease, and emerging evidence that stromal lesions are present in patients with Paget's disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas [4].
• Epstein-Barr virus (EBV)-immortalized B-cell lymphocytes were established from 13 patients, giving access to functional analysis of the gene and the SQSTM1/p62 expressions using real-time PCR and Western blot [5].

Psychiatry related information on SQSTM1

• We examined the immunoreactivity of p62 in five cases of frontotemporal dementia (FTD) with ubiquitin-positive, tau-negative inclusions [6].
• p62 is a ubiquitously expressed phosphoprotein that interacts with a number of signaling molecules and a major component of neurofibrillary tangles in the brain of Alzheimer's disease patients [7].

High impact information on SQSTM1

• The p80 WD40 domain does not participate in p60 dimerization, but localizes to centrosomes in transfected mammalian cells [8].
• In both infected and uninfected cells, p60 was found in a complex with the cdc2 protein kinase [9].
• The phosphorylation state of p34, its association with p62, and the protein kinase activity of the complex were each subject to cell cycle regulation [10].
• It is now shown that p60 is detected in cells of five mammalian species transformed by m1MSV, indicating that p60 is specified by this genome [11].
• It was previously demonstrated that the 60,000 dalton (p60) precursor-like polyprotein containing murine p30 was a constituent of the feline leukemia virus pseudotype of Moloney sarcoma virus [m1MSV(FeLV)] [11].

Chemical compound and disease context of SQSTM1

• Stimulation of a B lymphoma cell line, A20, with intact anti-IgG antibody induced a direct, SH2-mediated association between Csk and a 62-kD phosphotyrosine-containing protein that was identified as RasGTPase-activating protein-associated p62 (GAP-A.p62) [12].

Biological context of SQSTM1

• p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death [13].
• Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences [14].
• CONCLUSIONS: These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history [15].
• We identified three novel SQSTM1 mutations in PDB, conducted functional and structural analyses of all PDB-causing mutations, and studied the relationship between genotype and phenotype [14].
• Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G) [15].

Anatomical context of SQSTM1

• A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62 gene mutations responsible for pagetic osteoclast development and disease severity are unclear [16].
• The proteasome inhibitor PSI increased p62 mRNA and protein; however, PSI treatment of breast epithelial cells transfected with the p62 promoter did not affect promoter activity [3].
• Differential effects of B cell receptor and B cell receptor-FcgammaRIIB1 engagement on docking of Csk to GTPase-activating protein (GAP)-associated p62 [12].
• p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases [17].
• Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent [18].

Associations of SQSTM1 with chemical compounds

• We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations [19].
• In addition to p60, a protein of 190 kDa coprecipitated with Csk, and both proteins were phosphorylated on tyrosine residues by the immunocomplex [20].
• Sequence analysis identified the SMI 31 and MPM-2 immunoreactive material as p62, indicating that p62 is a major constituent of IHBs. p62 is an only recently discovered protein that is a phosphotyrosine-independent ligand of the SH2 domain of p56(lck), a member of the c-src family of cytoplasmic kinases [18].
• Cycloheximide-induced enhanced transcription suggests the immediate early response of the p62 gene [21].
• The mutation detected in one virus involves replacement of the normal Glu-378 in p60c-src by Gly, whereas the p60 of the other transforming virus has Phe instead of the normal Ile-441 [22].

Regulatory relationships of SQSTM1

• Here we show that PDEF stimulates the p62 promoter through at least two sites, and likely acts as a coactivator [3].
• Altogether, these findings reveal Lys(63)-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting [23].

Other interactions of SQSTM1

• We examined the immunoreactivity of ubiquitin-binding protein p62 and its association with ubiquitin (Ub), alpha-synuclein, and paired helical filament (PHF)-tau in the affected brain areas of human tauopathies and synucleinopathies [2].
• Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone [24].
• Ajuba recruits TRAF6 to p62 and in vitro activates PKCzeta activity and is a substrate of PKCzeta [25].
• Previous work demonstrated an essential role for the atypical protein kinase C interacting protein, p62, in neurotrophin survival and differentiation signaling [26].
• It is proposed that the 5q35-qter and 5q31 loci be named "PDB3" and "PDB4," respectively [27].
• Our results support the proposal that LC3 is responsible for recruiting p62 into autophagosomes, a process mediated by phenylalanine 52, located within the ubiquitin core, and the N-terminal region of the protein [28].

Analytical, diagnostic and therapeutic context of SQSTM1

• METHODS: We performed a case-control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation [29].
• Sequence analysis of the gene encoding sequestosome 1 revealed a single base pair deletion (1215delC) segregating with the majority of affected members in the pedigree [30].
• Specifically, we immobilized a 16-basepair double-stranded DNA region of the SQSTM1 promoter to the Texas Instruments Spreeta, a surface plasmon resonance sensor [31].
• To determine which subunit of PIK (p110 or p85) p62 associates with, we first immunoprecipitated insulin-treated cell lysates with alpha-p110 and subsequently immunoprecipitated with alpha-p85 followed by Western blotting analysis with anti-phosphotyrosine antibody (alpha-PY) [32].
• Indirect immunofluorescence showed that, like p62, p90 localized to the cytoplasm in cultured cells and mouse fetal, but not adult liver [33].

References