scholarly journals Sequential posttranslational modifications regulate PKC degradation

2016 ◽  
Vol 27 (2) ◽  
pp. 410-420 ◽  
Author(s):  
Yan Wang ◽  
Yangbo Wang ◽  
Huijun Zhang ◽  
Yingwei Gao ◽  
Chao Huang ◽  
...  
Keyword(s):  
Cross Talk ◽  
Posttranslational Modifications ◽  
Protein Function ◽  
Regulatory Mechanism ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Different Types ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Cross-talk among different types of posttranslational modifications (PTMs) has emerged as an important regulatory mechanism for protein function. Here we elucidate a mechanism that controls PKCα stability via a sequential cascade of PTMs. We demonstrate that PKCα dephosphorylation decreases its sumoylation, which in turn promotes its ubiquitination and ultimately enhances its degradation via the ubiquitin-proteasome pathway. These findings provide a molecular explanation for the activation-induced down-regulation of PKC proteins.

scholarly journals The RING Domain of cIAP1 Mediates the Degradation of RING-bearing Inhibitor of Apoptosis Proteins by Distinct Pathways

2008 ◽  
Vol 19 (7) ◽  
pp. 2729-2740 ◽  
Author(s):  
Herman H. Cheung ◽  
Stéphanie Plenchette ◽  
Chris J. Kern ◽  
Douglas J. Mahoney ◽  
Robert G. Korneluk
Keyword(s):  
Fas Ligand ◽  
Ring Domain ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Proteins ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Apoptosis Proteins

The Inhibitor of Apoptosis proteins (IAPs) are key repressors of apoptosis. Several IAP proteins contain a RING domain that functions as an E3 ubiquitin ligase involved in the ubiquitin-proteasome pathway. Here we investigated the interplay of ubiquitin-proteasome pathway and RING-mediated IAP turnover. We found that the CARD-RING domain of cIAP1 (cIAP1-CR) is capable of down-regulating protein levels of RING-bearing IAPs such as cIAP1, cIAP2, XIAP, and Livin, while sparing NAIP and Survivin, which do not possess a RING domain. To determine whether polyubiquitination was required, we tested the ability of cIAP1-CR to degrade IAPs under conditions that impair ubiquitination modifications. Remarkably, although the ablation of E1 ubiquitin-activating enzyme prevented cIAP1-CR–mediated down-regulation of cIAP1 and cIAP2, there was no impact on degradation of XIAP and Livin. XIAP mutants that were not ubiquitinated in vivo were readily down-regulated by cIAP1-CR. Moreover, XIAP degradation in response to cisplatin and doxorubicin was largely prevented in cIAP1-silenced cells, despite cIAP2 up-regulation. The knockdown of cIAP1 and cIAP2 partially blunted Fas ligand-mediated down-regulation of XIAP and protected cells from cell death. Together, these results show that the E3 ligase RING domain of cIAP1 targets RING-bearing IAPs for proteasomal degradation by ubiquitin-dependent and -independent pathways.

Abstract 486: Down-regulation of type 1 cGMP-dependent Protein Kinase by the ubiquitin/proteasome pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
NUPUR DEY ◽  
Jennifer L Busch ◽  
Sharron H Francis ◽  
Jackie D Corbin ◽  
Thomas M Lincoln
Keyword(s):  
Protein Kinase ◽  
26S Proteasome ◽  
Down Regulation ◽  
Dependent Protein Kinase ◽  
Ubiquitin Proteasome Pathway ◽  
Cgmp Dependent Protein Kinase ◽  
Ubiquitin Proteasome ◽  
Dependent Protein ◽  
Proteasome Pathway

Type 1 cGMP-dependent protein kinase (PKG-I) is a widely expressed serine/threonine protein kinase, and is a major mediator of nitric oxide (NO) signaling in vascular smooth muscle cells (VSMC). PKG-I level is highly variable in VSMC and several studies have shown that atherogenic inflammatory cytokines lower the steady-statel levels of PKG-I. The mechanism of action of down-regulation is not well defined, but induction of type II NO synthase (iNOS) and subsequent persistent elevation of cGMP appear to contribute to PKG-I down regulation. In the present study, we examined the role of the ubiquitin/proteasome pathway in PKG-Iα down-regulation in response to elevated cGMP. Incubation of cultured VSMC with 8-Br-cGMP for 6–12 hr lowered PKG-I expression as assessed by western blotting. To further examine the mechanism, Cos7 cells, which do not express PKG-I mRNA or protein, were transfected with PKG-Iα/pcDNA vector and incubated with 8-Br-cGMP. 8-Br-cGMP suppressed PKG-Iα protein level in Cos7 cells (half-maximal concentration = 250 μM). Pretreatment of these cells with the proteasome inhibitor, MG132, followed by 8-Br-cGMP treatment prevented the decline suggesting the involvement of the ubiquitin/26S proteasome pathway. Immunoprecipitation of PKG-I followed by immunoblotting with anti-ubiquitin revealed multiple ubiquitinated PKG bands in the 8-Br-cGMP treated samples but not in untreated samples. Ubiquitination and down-regulation were also inhibited by the specific PKG-I catalytic inhibitor DT-2, suggesting the possible involvement of PKG autophosphorylation in the 8-Br-cGMP induced down-regulation. Mutation of the PKG-Iα autophosphorylation sites to alanines was performed to identify the phosphorylated site responsible for cGMP-dependent ubiquitination. In contrast to wild type PKG-Iα, PKG-Iα S64A, but not the S50A mutant, was not down-regulated by 8-Br-cGMP suggesting that autophosphorylation of serine-64 is required for the ubiquitination and down-regulation of PKG-I. Autophosphorylation and cGMP-mediated down-regulation of PKG-I may be an important mechanism to control excess cGMP signaling in VSMC.

scholarly journals Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway

1999 ◽  
Vol 339 (2) ◽  
pp. 453 ◽  
Author(s):  
Jon OBERDORF ◽  
Jack M. WEBSTER ◽  
Chang Cheng ZHU ◽  
Su Ge LUO ◽  
Richard J.H. WOJCIKIEWICZ
Keyword(s):  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Inositol 1,4,5 Trisphosphate ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

IMPLICATION OF THE UBIQUITIN-PROTEASOME PATHWAY IN THE VEGF-DEPENDENT DOWN-REGULATION OF VEGFR-2 IN ENDOTHELIAL CELLS

2004 ◽  
Vol 13 (3) ◽  
pp. 46
Author(s):  
Martine Duval ◽  
Sara Bédard-Goulet ◽  
Chantal Delisle ◽  
Jean-Philippe Gratton
Keyword(s):  
Endothelial Cells ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

scholarly journals Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway

1999 ◽  
Vol 339 (2) ◽  
pp. 453-461 ◽  
Author(s):  
Jon OBERDORF ◽  
Jack M. WEBSTER ◽  
Chang Cheng ZHU ◽  
Su Ge LUO ◽  
Richard J. H. WOJCIKIEWICZ
Keyword(s):  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Proteasome Inhibitors ◽  
Cell Types ◽  
Type I ◽  
Down Regulation ◽  
Ubiquitin Proteasome Pathway ◽  
Inositol 1,4,5 Trisphosphate ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(1,4,5)P3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P3 receptors are membrane-bound, (v) that Ins(1,4,5)P3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P3 concentration persistently, and (vi) that a portion of cellular Ins(1,4,5)P3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4,5)P3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P3 to its receptor.

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