CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt

  title={CYLD negatively regulates transforming growth factor-$\beta$-signalling via deubiquitinating Akt},
  author={Jae Hyang Lim and Hirofumi Jono and Kensei Komatsu and Chang Hoon Woo and Jiyun Lee and Masanori Miyata and Takashi Matsuno and Xiangbin Xu and Yu-xian Huang and Wenhong Zhang and Soo-Hyun Park and Yu-Il Kim and Yoo Duk Choi and Huahao Shen and Kyung-Sun Heo and Hao-dong Xu and Patricia A. Bourne and Tomoaki Koga and Haidong Xu and Chen Yan and Binghe Wang and Lin-Feng Chen and Xin-Hua Feng and Jian-Dong Li},
  journal={Nature Communications},
Lung injury, whether induced by infection or caustic chemicals, initiates a series of complex wound-healing responses. If uncontrolled, these responses may lead to fibrotic lung diseases and loss of function. Thus, resolution of lung injury must be tightly regulated. The key regulatory proteins required for tightly controlling the resolution of lung injury have yet to be identified. Here we show that loss of deubiquitinase CYLD led to the development of lung fibrosis in mice after infection… 

CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-κB Inflammatory Signaling in Mesangial Cells

The present results support the involvement of CYLD in the regulation of NF-κB inflammatory signaling induced by elevated glucose, implicating CYLD as a potential therapeutic target of DN.

Cycles of Ubiquitination and Deubiquitination Critically Regulate Growth Factor–Mediated Activation of Akt Signaling

The findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in determining its plasma membrane localization and activation—and further identify CYLD as a molecular switch for these processes.

CYLD negatively regulates Hippo signaling by limiting Hpo phosphorylation in Drosophila.

Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD

It is shown that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD.

CYLD-mediated signaling and diseases.

This review explores a broad selection of current and past literature regarding CYLD's expression, function and regulation with emerging reports on its role in cardiovascular disease.

Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6.

It is demonstrated that the inhibitory Smad Smad6, but not Smad7, negatively regulates TGF-β1-induced activation of the TRAF6-TAK1-p38 MAPK/JNK pathway, a noncanonical TGF -β pathway.

Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88

It is demonstrated for the first time to the authors' knowledge that MyD88 protein undergoes lysine 63 (K63)-linked polyubiquitination, which is functionally critical for mediating TLR–MyD88-dependent signaling.

The role of the deubiquitinating enzyme CYLD and its substrate BCL-3 in solid tumors

CYLD down-regulation is a risk factor for development and progression of HCC mediated through activation of JNK1 (Less) and results suggest that SRF is a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of wild type MEF cells.



The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination

CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process.

CYLD: a tumor suppressor deubiquitinase regulating NF-κB activation and diverse biological processes

  • S-C Sun
  • Biology
    Cell Death and Differentiation
  • 2010
This work has shown that a tumor suppressor DUB, cylindromatosis (CYLD), has a predominant role in the regulation of NF-κB, a transcription factor that promotes cell survival and oncogenesis and is subject to different mechanisms of regulation.

Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB

It is reported here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD), having no known function, enhances activation of the transcription factor NF-κB, and this effect can be relieved by aspirin derivatives that inhibit NF-σB activity.

Transforming Growth Factor-β-Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via Mitogen-activated Protein Kinase (MAPK) Phosphatase-1-dependent Inhibition of p38 MAPK*

It is shown that nontypeable Haemophilus influenzae, a major human bacterial pathogen of otitis media and chronic obstructive pulmonary diseases, strongly induces up-regulation of MUC5AC mucin via activation of the Toll-like receptor 2-MyD88-dependent p38 path-way.

Regulation of TGF‐β family signaling by E3 ubiquitin ligases

Members of the transforming growth factor‐β (TGF‐β) family are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis.

CHIP Controls the Sensitivity of Transforming Growth Factor-β Signaling by Modulating the Basal Level of Smad3 through Ubiquitin-mediated Degradation*

Evidence is reported for a novel mechanism of regulating TGF-β sensitivity that depends on the role of CHIP (carboxyl terminus of Hsc70-interacting protein) in regulating the basal level of Smad3 via the ubiquitin-dependent degradation pathway.

CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members

Results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-κB that is required for appropriate cellular homeostasis of skin appendages.

Transforming Growth Factor-β-Smad Signaling Pathway Cooperates with NF-κB to Mediate NontypeableHaemophilus influenzae-induced MUC2 Mucin Transcription*

These data are the first to demonstrate the involvement of TGF-β receptor-mediated signaling in bacteria-induced up-regulation of mucin transcription, bring insights into the novel role of T GF-β signaling in bacterial pathogenesis, and may lead to new therapeutic intervention of NTHi infections.

Dual function of MyD88 in RAS signaling and inflammation, leading to mouse and human cell transformation.

Results show that in addition to its role in inflammation, MyD88 plays what the authors believe to be a crucial direct role in RAS signaling, cell-cycle control, and cell transformation.