Lysine 63 Polyubiquitination of the Nerve Growth Factor Receptor TrkA Directs Internalization and Signaling

Geetha, Thangiah; Jiang, Jianxiong; Wooten, Marie W.

doi:10.1016/j.molcel.2005.09.014

Cited by 247 publications

(298 citation statements)

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“…Both TrkB and TrkC were examined to determine if this consensus pattern existed in the other members of the Trk family, since both TrkB and TrkC have been reported to be ubiquitinated by TRAF6/p62 [9]. Interestingly, Lysines at 811 in TrkB and 602 and 815 in TrkC possessed a similar pattern in their flanking amino acids homologous to the sequence observed in TrkA and NRIF (Fig.…”

Section: Resultsmentioning

confidence: 89%

“…Two independent reports have identified TrkA [9] and NRIF [10] as TRAF6/p62 substrates. Moreover, the specific lysine residue in both these proteins that serve as the ubiquitin acceptor site was identified.…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…As control, ubiquitination of WT-TrkA and K485R TrkA mutant [9] was examined. Maximum polyubiquitination of Trk receptors has been observed after 15 min treatment with neurotrophins [15].…”

Section: Traf6 Ubiquitinates Trkb At Lysine 811mentioning

confidence: 99%

“…Recent findings from our lab have revealed that both TrkA [9] and the neurotrophin receptor interacting factor (NRIF) [10] are K63-polyubiquitinated by the TRAF6/p62 complex. Mutation analyses of these proteins identified a single acceptor lysine residue that serves as the recognition site for polyubiquitination.…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

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

confidence: 99%

“…As control, ubiquitination of WT-TrkA and K485R TrkA mutant [9] was examined. Maximum polyubiquitination of Trk receptors has been observed after 15 min treatment with neurotrophins [15].…”

Section: Traf6 Ubiquitinates Trkb At Lysine 811mentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of a consensus site for TRAF6/p62 polyubiquitination

Jadhav

Geetha

Jiang

et al. 2008

Biochemical and Biophysical Research Communications

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p62/SQSTM1 promotes rapid ubiquitin conjugation to target proteins after endosome rupture during xenophagy

et al. 2018

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Autophagy is a bulk degradation pathway, and selective autophagy to remove foreign entities is called xenophagy. The conjugation of ubiquitin to target pathogens is an important process in xenophagy but when and where this ubiquitination occurs remains unclear. Here, we analyzed the temporal sequence and subcellular location of ubiquitination during xenophagy using time‐lapse observations, with polystyrene beads mimicking invading pathogens. Results revealed accumulation of a ubiquitination marker around the beads within 3 min after endosome rupture. Recruitment of ubiquitin to the beads was significantly delayed in p62‐knockout murine embryonic fibroblast cells, and this delay was rescued by ectopic p62 expression. Ectopic expression of a phosphorylation‐mimicking p62 mutated at serine residue 405 (equivalent to human serine residue 403) rescued this delay, but its unphosphorylated form did not. These results indicate that ubiquitination mainly occurs after endosome rupture and suggest that p62, specifically the phosphorylated form, promotes ubiquitin conjugation to target proteins in xenophagy.

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Growth Factors: Protein Processing, Endocytosis, and Intracellular Sorting

Duex

Sorkin

2010

Encyclopedia of Industrial Biotechnology

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Growth factor (GF) receptors are extracellular receptors which, when bound by growth factors, initiate intracellular signaling for promoting cellular proliferation, survival, and differentiation. The amount of signaling is generally controlled by both the levels of growth factor and the levels of GF receptors present in the cell, particularly at the cell surface. This review will focus on the mechanisms of endocytosis and postendocytic trafficking that serve to control the levels of GF receptors. The classical experimental system used to investigate these processes is the endocytosis of GF receptors that possess intrinsic tyrosine kinase activity, known as receptor tyrosine kinases (RTKs). We will use the prototypical RTK, epidermal growth factor receptor (EGFR), as the model GF receptor in this discussion since much of the data leading to the current understanding of GF receptor endocytosis was generated using this receptor.Growth factor (GF) receptors are extracellular receptors which, when bound by growth factors, initiate intracellular signaling for promoting cellular proliferation, survival, and differentiation. The amount of signaling is generally controlled by both the levels of growth factor and the levels of GF receptors present in the cell, particularly at the cell surface. This review will focus on the mechanisms of endocytosis and postendocytic trafficking that serve to control the levels of GF receptors. The classical experimental system used to investigate these processes is the endocytosis of GF receptors that possess intrinsic tyrosine kinase activity, known as receptor tyrosine kinases (RTKs). We will use the prototypical RTK, epidermal growth factor receptor (EGFR), as the model GF receptor in this discussion since much of the data leading to the current understanding of GF receptor endocytosis was generated using this receptor.

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Lysine 63 Polyubiquitination of the Nerve Growth Factor Receptor TrkA Directs Internalization and Signaling

Cited by 247 publications

References 52 publications

Identification of a consensus site for TRAF6/p62 polyubiquitination

Identification of a consensus site for TRAF6/p62 polyubiquitination

p62/SQSTM1 promotes rapid ubiquitin conjugation to target proteins after endosome rupture during xenophagy

Growth Factors: Protein Processing, Endocytosis, and Intracellular Sorting

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