Signal integration and diversification through the p62 scaffold protein

Moscat, Jorge; Diaz-Meco, Marı́a T.; Wooten, Marie W.

doi:10.1016/j.tibs.2006.12.002

Cited by 305 publications

(284 citation statements)

References 41 publications

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“…p62 can promote the translocation of TRAF6 into ubiquitin-rich foci, promoting TRAF6-mediated activation of NF-kB (Moscat et al, 2007). A20, which inhibits caspase-8 activation, also negatively regulates NF-kB activation by deubiquitylating RIP1 (Wertz et al, 2004).…”

Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

New insights into apoptosis signaling by Apo2L/TRAIL

2010

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Section: Recent Advances In Understanding Apoptosis Initiationmentioning

confidence: 99%

New insights into apoptosis signaling by Apo2L/TRAIL

2010

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“…This was paralleled by increases of LC3B-II and p62 protein level, both closely associated with autophagy. Increase of p62 protein levels has been found in the aging retina (Rodrigues-Muela et al, 2013) and is known to interact with LC3B-I and ubiquitinated proteins, perhaps acting as an autophagy receptor (Moscat et al, 2007).…”

Section: Cyclic Illumination Causes Additional Stress and Induces Autmentioning

confidence: 99%

“…LC3B-II is consequently closely associated with the quantity of autophagosomes (Kabeya et al, 2000). Other regulators of autophagy involve the ubiquitin-and LC3B-binding protein p62 (Moscat et al, 2007) and Beclin-1, which is a regulator for initial autophagosome formation (Pickford et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

et al. 2014

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Abbreviations: AMD, age-related macular degeneration; BSA, bovine serum albumin; CHOP, C/EBP homology protein; CtBP2, C-terminal binding protein 2; ER, endoplasmic reticulum; GRP78/BiP, glucoseregulated protein 78kDa/Binding immunoglobulin protein, INL, inner nuclear layer; IPL, inner plexiform layer; LC3B, microtubule-associated protein light chain 3B; mTOR, mammalian target of rapamycin; ONL, outer nuclear layer; OPL, outer nuclear layer; PBS, phosphate buffered saline; PNA, peanut agglutinin; p62/SQSTM1; nucleoporin p62/sequestosom 1; PSD-95, postsynaptic density protein 95; rd1, retinal degeneration 1; RPE, retinal pigment epithelium; UPS, ubiquitin-proteasome system; 2 AbstractThe aim of this study was to investigate rod and cone photoreceptor degeneration in organotypic cultures of adult porcine retina. Our hypothesis was that the photoreceptors accumulate opsins, which, together with exposure to cyclic dim light illumination, induce autophagy and endoplasmic reticulum stress (ER-stress) to overcome damaging protein overload. For this purpose, retinas were cultured for 48 h and 72 h during which they were illuminated with dim light for 8 h/day; specimens were analyzed by means of immunohistochemistry, western blot and transmission electron microscopy. ER-stress and photoreceptor degeneration was observed in conventionally cultured retinas. The additional stress in the form of dim light illumination for 8 h/day resulted in increased levels of the ER-stress markers GRP78/BiP and CHOP, as well as increased level of active caspase-12. Increased autophagic processes in cone and rod photoreceptors were detected by LC3B-II increases and occurrence of autophagosomes at the ultrastructural level. Illumination also resulted in altered protein expression for autophagy inducers such as p62 and Beclin-1. Moreover, there was a decrease in phosphorylated mammalian target of rapamycin (mTOR), which further indicate an increase of autophagy. Rod and cone photoreceptors in retinas from a diurnal animal that were exposed to dim light illumination in vitro displayed autophagy and ER-stress processes. In particular, these processes resulted in decreased protein levels for rhodopsin.3

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“…P62 serves as an adaptor bridge to recruit TRAF6 through its TRAF6 binding site [3,8,9]. Therefore, studies were undertaken to examine whether mutation at the primary ubiquitination site in the TrkB receptor impairs formation of a TRAF6/p62 signaling complex.…”

Section: Mutation Impairs P62's Ability To Link Trkb To Traf6mentioning

confidence: 99%

“…Cytoplasmic protein p62 was identified as an interacting partner of atypical protein kinase C (PKC) [2] and has been shown to contain several protein-protein interacting modules that enable the protein to serve as a scaffold for activation of the transcription factor NF-κB [3]. The multidomain protein structure of p62 is suggestive of diverse protein-protein interactions and its link in cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Identification of a consensus site for TRAF6/p62 polyubiquitination

Jadhav

Geetha

Jiang

et al. 2008

Biochemical and Biophysical Research Communications

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Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an ubiquitin ligase that regulates a diverse array of physiological processes via forming Lys-63 linked polyubiquitin chains. In this study, the lysine selection process for TRAF6/p62 ubiquitination was examined. The protein sequence of two characterized TRAF6/p62 substrates, NRIF and TrkA, revealed a conserved consensus pattern for the ubiquitination site of these two TRAF6 substrates. The consensus pattern established in the verified substrates was common to the other Trk receptor family members, TrkB and TrkC. Interestingly, Lysine 811 in TrkB was selected for ubiquination, and mutation of Lysine 811 diminished the formation of TRAF6/p62 complex that is necessary for effective ubiquination. Moreover, downstream signaling was affected upon binding of BDNF to the mutant TrkB receptor. These findings reveal a possible selection process for targeting a specific lysine residue by a single E3 ligase and underscore the role of the scaffold, p62, in this process. KeywordsUbiquitination; Ub ligase; TRAF6; p62; Trk Many adaptors have been identified in studies of other neuronal tyrosine kinases that may also prove to function in Trk receptor-mediated signaling [1]. Cytoplasmic protein p62 was identified as an interacting partner of atypical protein kinase C (PKC) [2] and has been shown to contain several protein-protein interacting modules that enable the protein to serve as a scaffold for activation of the transcription factor NF-κB [3]. The multidomain protein structure of p62 is suggestive of diverse protein-protein interactions and its link in cellular functions. The functional motifs in p62 include a Phox and Bem1p domain (PB1) domain that embeds an octicosapeptide Phox, Cdc and the atypical PKC-interaction domain (AID) (OPCA) motif, a ZZ zinc finger, a binding site for Tumor necrosis factor Receptor-Associated Factor 6 (TRAF6), two PEST sequences, and an Ubiquitin-associated (UBA) domain [4]. The Cterminal ubiquitin-associated domain (UBA) was discovered to bind non-covalently to ubiquitin [5]. In vitro binding studies have unveiled p62 as a unique ubiquitin-binding protein, which binds polyubiquitin non-covalently through its C-terminus [6].Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes. E3 Ub ligases are known to interact with specific substrates either directly or through adaptor proteins. *Corresponding author. Fax: +1 (334) 844-5255, Email address: wootemw@auburn.edu (M. Wooten). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . High substrate specificity of the ...

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Signal integration and diversification through the p62 scaffold protein

Cited by 305 publications

References 41 publications

New insights into apoptosis signaling by Apo2L/TRAIL

New insights into apoptosis signaling by Apo2L/TRAIL

Autophagy and ER-stress contribute to photoreceptor degeneration in cultured adult porcine retina

Identification of a consensus site for TRAF6/p62 polyubiquitination

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