p62 Functions as a p38 MAP Kinase Regulator

Sudo, Tatsuhiko; Maruyama, Masumi; Osada, Hiroyuki

doi:10.1006/bbrc.2000.2333

Cited by 41 publications

(30 citation statements)

References 19 publications

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“…All of these signals were significantly decreased in adipocyte-specific p62 -/-mice, suggesting that p62 likely controls mitochondrial function via the p38/Ppargc1a pathway. Notably, this assumption is consistent with reports indicating that p62 binds p38 via its C-terminal domain and that p62 is colocalized with phosphorylated p38 in the nuclei (32)(33)(34).…”

Section: Methodssupporting

confidence: 92%

“…Several studies have previously shown that p38 MAPK is crucial for sympathetic nervous system-mediated (SNS-mediated) activation of BAT nonshivering thermogenesis and Ucp1 function (7,(29)(30)(31). Notably, by screening a HeLa cDNA library, Sudo and colleagues previously identified p62 as a p38-binding protein (32). Following up on that finding, Kawai and colleagues identified 2 p62 binding domains in p38.…”

Section: Discussionmentioning

confidence: 99%

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p62 Links β-adrenergic input to mitochondrial function and thermogenesis

Müller¹,

Lee²,

Jastroch³

et al. 2012

J. Clin. Invest.

111

103

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The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to β-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1α, DIO2, NRF1, CYTC, COX2, ATP5β, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.

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Section: Methodssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

p62 Links β-adrenergic input to mitochondrial function and thermogenesis

Müller¹,

Lee²,

Jastroch³

et al. 2012

J. Clin. Invest.

111

103

View full text Add to dashboard Cite

show abstract

“…These phosphorylated residues later serve as sites for additional effector factors, and enzymes to bind and propagate the signal downstream. This leads to rapid and sustained activation of various signaling pathways, including the Ras/MAPK pathway and the AKT pathway [16]. The ability of NGF and BDNF to stimulate downstream MAPK and AKT signaling as compared to their mutant counterparts was examined.…”

Section: Receptor Ubiquitination Implicated In Regulation Of Trkb Dowmentioning

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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“…Several diverse roles for p62 have been proposed based on the rat p62 homolog zeta protein kinase C (PKC)-interacting protein (ZIP) and the mouse proteins A170 and signal transduction adapter protein (STAP), which share approximately 90% homology to each other (Geetha and Wooten, 2002). These functions include acting as a scaffold linker protein in the NF-kB signal transduction pathway (Sanz et al, 1999(Sanz et al, , 2000, K + channel modifier (Gong et al, 1999), and nuclear factor (Rachubinski et al, 1999;Sudo et al, 2000;Geetha and Wooten, 2002). The ability of p62 to bind noncovalently to ubiquitin and several signaling proteins suggests that p62 may play a regulatory role connected to the ubiquitin pathway.…”

Section: Introductionmentioning

confidence: 99%