The role of ubiquitin in neurotrophin receptor signalling and sorting

2006 ◽  
Vol 34 (5) ◽  
pp. 757-760 ◽  
Author(s):  
M.W. Wooten ◽  
T. Geetha
Keyword(s):  
Neurotrophin Receptor ◽  
Tumour Necrosis Factor Receptor ◽  
Receptor Kinase ◽  
Polyubiquitin Chains ◽  
Receptor Signalling ◽  
Kinase C ◽  
Ubiquitin Conjugating Enzyme ◽  
P75 Receptor ◽  
Necrosis Factor

NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62–TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.

Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2

2008 ◽  
Vol 36 (3) ◽  
pp. 449-452 ◽  
Author(s):  
Andrew G. Bowie
Keyword(s):  
Vaccinia Virus ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Relative Role ◽  
Toll Like Receptor ◽  
Turn On ◽  
Receptor Signalling ◽  
Necrosis Factor

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.

scholarly journals RANK receptor oligomerisation in the regulation of NFκB signalling

2014 ◽  
Vol 53 (1) ◽  
pp. 81-91 ◽  
Author(s):  
S Das ◽  
I Sepahi ◽  
A Duthie ◽  
S Clark ◽  
J C Crockett
Keyword(s):  
Functional Study ◽  
Tumour Necrosis Factor Receptor ◽  
Transcription Activator ◽  
Targeted Disruption ◽  
Binding Motifs ◽  
Receptor Activator ◽  
Formation Function ◽  
Prevention Of Osteoporosis ◽  
Necrosis Factor

The interaction of receptor activator of NFκB (RANK), a member of the tumour necrosis factor receptor superfamily, with RANK ligand is crucial for the formation, function and survival of osteoclasts. The role of the cytoplasmic oligomerisation domain (pre-ligand assembly domain; PLAD or ‘IVVY’ motif) in the ligand-dependent activation of downstream NFκB signalling has not been studied previously. The discovery of truncating mutations ofTNFRSF11A(W434X and G280X that lack the PLAD) as the cause of rare cases of osteoclast-poor osteopetrosis offered the opportunity for functional study of this region. Recapitulating the W434X mutation by transcription activator-like effector nuclease (TALEN)-mediated targeted disruption ofTnfrsf11awithin the region homologous to W434X in the mouse macrophage-like cell line RAW264.7 impaired formation of osteoclast-like cells. Using overexpression studies, we demonstrated that, in contrast to WT-RANK, the absence of the PLAD in G280X-RANK and W434X-RANK prevented ligand-independent but not ligand-dependent oligomerisation. Cells expressing W434X-RANK, in which only two of the three TRAF6-binding motifs are present, continued to exhibit ligand-dependent NFκB signalling. Hence, the absence of the PLAD did not prevent ligand-induced trimerisation and subsequent NFκB activation of RANK, demonstrating that therapeutic targeting of the PLAD in the prevention of osteoporosis may not be as effective as proposed previously.

Nocardia fractions, NLD and NWSM, induce tumor necrosis factor-α secretion in human monocytes: Role of protein kinase C

1993 ◽  
Vol 23 (7) ◽  
pp. 1582-1587 ◽  
Author(s):  
Jean Louis Mege ◽  
Thiery Jacob ◽  
Pierre Bongrand ◽  
Christian Capo ◽  
Evguenine B. Myssiakine ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Human Monocytes ◽  
Kinase C ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals TNF receptor signalling in autoinflammatory diseases

2019 ◽  
Vol 31 (10) ◽  
pp. 639-648 ◽  
Author(s):  
Heledd H Jarosz-Griffiths ◽  
Jonathan Holbrook ◽  
Samuel Lara-Reyna ◽  
Michael F McDermott
Keyword(s):  
Molecular Mechanisms ◽  
Innate Immune ◽  
Autoinflammatory Diseases ◽  
Tumour Necrosis Factor Receptor ◽  
Therapeutic Approaches ◽  
Ubiquitin Chain ◽  
Receptor Signalling ◽  
Target Disease ◽  
Necrosis Factor ◽  
Disease Present

Abstract Autoinflammatory syndromes are a group of disorders characterized by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these diseases arise from defects in the tumour necrosis factor receptor (TNFR) signalling pathway leading to elevated levels of inflammatory cytokines. Elucidation of the molecular mechanisms of these recently defined autoinflammatory diseases has led to a greater understanding of the mechanisms of action of key molecules involved in TNFR signalling, particularly those involved in ubiquitination, as found in haploinsufficiency of A20 (HA20), otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) and linear ubiquitin chain assembly complex (LUBAC) deficiency. In this review, we also address other TNFR signalling disorders such as TNFR-associated periodic syndrome (TRAPS), RELA haploinsufficiency, RIPK1-associated immunodeficiency and autoinflammation, X-linked ectodermal dysplasia and immunodeficiency (X-EDA-ID) and we review the most recent advances surrounding these diseases and therapeutic approaches currently used to target these diseases. Finally, we explore therapeutic advances in TNF-related immune-based therapies and explore new approaches to target disease-specific modulation of autoinflammatory diseases.

scholarly journals T-type Ca 2+ channels are required for enhanced sympathetic axon growth by TNFα reverse signalling

Open Biology ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. 160288 ◽  
Author(s):  
Lilian Kisiswa ◽  
Clara Erice ◽  
Laurent Ferron ◽  
Sean Wyatt ◽  
Catarina Osório ◽  
...  
Keyword(s):  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Axon Growth ◽  
Tumour Necrosis Factor Receptor ◽  
Kinase C ◽  
Cultured Sympathetic Neurons ◽  
Sympathetic Axon ◽  
Pkc Activation ◽  
Cell Somata ◽  
Necrosis Factor

Tumour necrosis factor receptor 1 (TNFR1)-activated TNFα reverse signalling, in which membrane-integrated TNFα functions as a receptor for TNFR1, enhances axon growth from developing sympathetic neurons and plays a crucial role in establishing sympathetic innervation. Here, we have investigated the link between TNFα reverse signalling and axon growth in cultured sympathetic neurons. TNFR1-activated TNFα reverse signalling promotes Ca 2+ influx, and highly selective T-type Ca 2+ channel inhibitors, but not pharmacological inhibitors of L-type, N-type and P/Q-type Ca 2+ channels, prevented enhanced axon growth. T-type Ca 2+ channel-specific inhibitors eliminated Ca 2+ spikes promoted by TNFα reverse signalling in axons and prevented enhanced axon growth when applied locally to axons, but not when applied to cell somata. Blocking action potential generation did not affect the effect of TNFα reverse signalling on axon growth, suggesting that propagated action potentials are not required for enhanced axon growth. TNFα reverse signalling enhanced protein kinase C (PKC) activation, and pharmacological inhibition of PKC prevented the axon growth response. These results suggest that TNFα reverse signalling promotes opening of T-type Ca 2+ channels along sympathetic axons, which is required for enhanced axon growth.

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