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SQSTM1  -  sequestosome 1

Homo sapiens

 
 
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Disease relevance of SQSTM1

 

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

 

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

 

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

  1. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hocking, L.J., Lucas, G.J., Daroszewska, A., Mangion, J., Olavesen, M., Cundy, T., Nicholson, G.C., Ward, L., Bennett, S.T., Wuyts, W., Van Hul, W., Ralston, S.H. Hum. Mol. Genet. (2002) [Pubmed]
  2. Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Kuusisto, E., Salminen, A., Alafuzoff, I. Neuroreport (2001) [Pubmed]
  3. p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells. Thompson, H.G., Harris, J.W., Wold, B.J., Lin, F., Brody, J.P. Oncogene (2003) [Pubmed]
  4. Osteosarcoma in Paget's Disease of Bone. Hansen, M.F., Seton, M., Merchant, A. J. Bone Miner. Res. (2006) [Pubmed]
  5. Paget's Disease of Bone in the French Population: Novel SQSTM1 Mutations, Functional Analysis, and Genotype-Phenotype Correlations. Collet, C., Michou, L., Audran, M., Chasseigneaux, S., Hilliquin, P., Bardin, T., Lemaire, I., Cornélis, F., Launay, J.M., Orcel, P., Laplanche, J.L. J. Bone Miner. Res. (2007) [Pubmed]
  6. Neuronal and glial inclusions in frontotemporal dementia with or without motor neuron disease are immunopositive for p62. Arai, T., Nonaka, T., Hasegawa, M., Akiyama, H., Yoshida, M., Hashizume, Y., Tsuchiya, K., Oda, T., Ikeda, K. Neurosci. Lett. (2003) [Pubmed]
  7. p62 modulates Akt activity via association with PKCzeta in neuronal survival and differentiation. Joung, I., Kim, H.J., Kwon, Y.K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  8. Katanin, a microtubule-severing protein, is a novel AAA ATPase that targets to the centrosome using a WD40-containing subunit. Hartman, J.J., Mahr, J., McNally, K., Okawa, K., Iwamatsu, A., Thomas, S., Cheesman, S., Heuser, J., Vale, R.D., McNally, F.J. Cell (1998) [Pubmed]
  9. A 60 kd cdc2-associated polypeptide complexes with the E1A proteins in adenovirus-infected cells. Giordano, A., Whyte, P., Harlow, E., Franza, B.R., Beach, D., Draetta, G. Cell (1989) [Pubmed]
  10. Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement. Draetta, G., Beach, D. Cell (1988) [Pubmed]
  11. Cells transformed by certain strains of Moloney sarcoma virus contain murine p60. Robey, W.G., Oskarsson, M.K., Woude, G.F., Naso, R.B., Arlinghaus, R.B., Haapala, D.K., Fischinger, P.J. Cell (1977) [Pubmed]
  12. Differential effects of B cell receptor and B cell receptor-FcgammaRIIB1 engagement on docking of Csk to GTPase-activating protein (GAP)-associated p62. Vuica, M., Desiderio, S., Schneck, J.P. J. Exp. Med. (1997) [Pubmed]
  13. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., Johansen, T. J. Cell Biol. (2005) [Pubmed]
  14. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. Hocking, L.J., Lucas, G.J., Daroszewska, A., Cundy, T., Nicholson, G.C., Donath, J., Walsh, J.P., Finlayson, C., Cavey, J.R., Ciani, B., Sheppard, P.W., Searle, M.S., Layfield, R., Ralston, S.H. J. Bone Miner. Res. (2004) [Pubmed]
  15. Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent. Lucas, G.J., Hocking, L.J., Daroszewska, A., Cundy, T., Nicholson, G.C., Walsh, J.P., Fraser, W.D., Meier, C., Hooper, M.J., Ralston, S.H. J. Bone Miner. Res. (2005) [Pubmed]
  16. Etiologic factors in Paget's disease of bone. Reddy, S.V. Cell. Mol. Life Sci. (2006) [Pubmed]
  17. p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases. Zatloukal, K., Stumptner, C., Fuchsbichler, A., Heid, H., Schnoelzer, M., Kenner, L., Kleinert, R., Prinz, M., Aguzzi, A., Denk, H. Am. J. Pathol. (2002) [Pubmed]
  18. Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent. Stumptner, C., Heid, H., Fuchsbichler, A., Hauser, H., Mischinger, H.J., Zatloukal, K., Denk, H. Am. J. Pathol. (1999) [Pubmed]
  19. Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin. Daroszewska, A., Hocking, L.J., McGuigan, F.E., Langdahl, B., Stone, M.D., Cundy, T., Nicholson, G.C., Fraser, W.D., Ralston, S.H. J. Bone Miner. Res. (2004) [Pubmed]
  20. Csk is constitutively associated with a 60-kDa tyrosine-phosphorylated protein in human T cells. Catipović, B., Schneck, J.P., Brummet, M.E., Marsh, D.G., Rafnar, T. J. Biol. Chem. (1996) [Pubmed]
  21. Immediate early response of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein. Lee, Y.H., Ko, J., Joung, I., Kim, J.H., Shin, J. FEBS Lett. (1998) [Pubmed]
  22. Activation of the transforming potential of p60c-src by a single amino acid change. Levy, J.B., Iba, H., Hanafusa, H. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  23. The role of ubiquitin in neurotrophin receptor signalling and sorting. Wooten, M.W., Geetha, T. Biochem. Soc. Trans. (2006) [Pubmed]
  24. Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone. Ciani, B., Layfield, R., Cavey, J.R., Sheppard, P.W., Searle, M.S. J. Biol. Chem. (2003) [Pubmed]
  25. The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complex. Feng, Y., Longmore, G.D. Mol. Cell. Biol. (2005) [Pubmed]
  26. Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling. Geetha, T., Wooten, M.W. J. Biol. Chem. (2003) [Pubmed]
  27. Paget disease of bone: mapping of two loci at 5q35-qter and 5q31. Laurin, N., Brown, J.P., Lemainque, A., Duchesne, A., Huot, D., Lacourcière, Y., Drapeau, G., Verreault, J., Raymond, V., Morissette, J. Am. J. Hum. Genet. (2001) [Pubmed]
  28. The N-terminus and Phe52 residue of LC3 recruit p62/SQSTM1 into autophagosomes. Shvets, E., Fass, E., Scherz-Shouval, R., Elazar, Z. J. Cell. Sci. (2008) [Pubmed]
  29. Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Eekhoff, E.W., Karperien, M., Houtsma, D., Zwinderman, A.H., Dragoiescu, C., Kneppers, A.L., Papapoulos, S.E. Arthritis Rheum. (2004) [Pubmed]
  30. Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Good, D.A., Busfield, F., Fletcher, B.H., Lovelock, P.K., Duffy, D.L., Kesting, J.B., Andersen, J., Shaw, J.T. Bone (2004) [Pubmed]
  31. Surface plasmon resonance-based sensors to identify cis-regulatory elements. Lin, L., Harris, J.W., Thompson, H.G., Brody, J.P. Anal. Chem. (2004) [Pubmed]
  32. Role of p85 subunit of phosphatidylinositol-3-kinase as an adaptor molecule linking the insulin receptor, p62, and GTPase-activating protein. Sung, C.K., Sánchez-Margalet, V., Goldfine, I.D. J. Biol. Chem. (1994) [Pubmed]
  33. Cloning and characterization of a novel 90 kDa 'companion' auto-antigen of p62 overexpressed in cancer. Soo Hoo, L., Zhang, J.Y., Chan, E.K. Oncogene (2002) [Pubmed]
 
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