Ubiquitin-dependent regulation of Cdc42 by XIAP

Murali, Arun; Shin, Jae-Young; Yurugi, Hajime; Krishnan, Aswini; Akutsu, Masato; Carpy, Alejandro; Maček, Boris; Rajalingam, Krishnaraj

doi:10.1038/cddis.2017.305

Cited by 24 publications

(39 citation statements)

References 25 publications

(26 reference statements)

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“…The effect of AKT-induced phosphorylation of Cdc42 on the interaction between FBXL19 and Cdc42 will be the focus of future research. Consistent with results from Murali et al (31), we also show that up-regulation of Cdc42 degradation reduces filopodia formation and tumor cell adhesion. RhoA, Cdc42, Rac1, and Rac3 belong to the Rho GTPase family and are the targets for FBXL19.…”

Section: Maintenance Of Protein Homeostasis Plays a Major Role In Thesupporting

confidence: 93%

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Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

et al. 2018

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Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation. FBXL19 is an unstable protein with a half-life of ∼3 h. FBXL19 can be polyubiquitinated, and the proteasome inhibitor MG-132 prolongs FBXL19 half-life, suggesting that FBXL19 degradation is mediated in the ubiquitin-proteasome system. FBXL19 can also be acetylated, and enhancing acetylation of FBXL19 by a deacetylase inhibitor reduces FBXL19 ubiquitination levels. Acetylation-mimic FBXL19 mutant exhibits a longer half-life than wild type. An acetyltransferase CBP catalyzes acetylation of FBXL19. Inhibition or down-regulation of CBP reduces FBXL19 stability, whereas it is increased in CBP-overexpressing cells. Taken together, the data indicate that CBP-mediated acetylation reduces ubiquitination and stabilizes FBXL19. Further, we demonstrate that FBXL19 targets small GTPase Cdc42 for its ubiquitination and degradation, whereas this effect is reversed by inhibition of CBP, suggesting that CBP increases the effect of SCF FBXL19 E3 ligase through acetylation and stabilization of FBXL19. Our study reveals a new molecular model for regulation of SCF E3 ligase function by acetylation and stabilization of its subunit F-box protein.-Wei, J., Dong, S., Yao, K., Martinez, M. F. Y. M., Fleisher, P. R., Zhao, Y., Ma, H., Zhao, J. Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F-box protein subunit.

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Section: Maintenance Of Protein Homeostasis Plays a Major Role In Thesupporting

confidence: 93%

“…Cdc42 is known to be polyubiquitinated (30). A recent study from Murali et al (31) shows that ubiquitin E3 ligase XIAP targets Cdc42 for its polyubiquitination and proteasomal degradation. In the current study, we reveal that another ubiquitin E3 ligase, SCF FBXL19, regulates Cdc42 stability.…”

Section: Maintenance Of Protein Homeostasis Plays a Major Role In Thementioning

confidence: 99%

Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

et al. 2018

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“…In this study, glutathione S-transferase (GST) conjugated OGT were used for a pull-down assay and a subsequent mass spectrometry (MS) analysis to identify the proteins that interact with OGT in HCT116 cells ( Supplementary Table S1). Among the proteins that interact with OGT, XIAP was studied because it plays an important role in tumorigenicity [7][8][9][10][11][12][13] . The pulled-down GST-OGT was immunoblotted with anti-XIAP antibody to confirm the interaction between GST-OGT and endogenous XIAP.…”

Section: Ogt Interaction With Xiapmentioning

confidence: 99%

“…XIAP plays a role in the cancer cells' resistance to anticancer drugs and studies on the antiapoptotic function of XIAP in cancer cells have been focused on depleting XIAP 6 . XIAP has many other roles besides inhibiting cancer cell death, so its involvement in cancer cell biology should be explored further [7][8][9][10][11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion

et al. 2020

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O-GlcNAc transferase (OGT) is an enzyme that catalyzes the O-GlcNAc modification of nucleocytoplasmic proteins and is highly expressed in many types of cancer. However, the mechanism regulating its expression in cancer cells is not well understood. This study shows that OGT is a substrate of the E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) which plays an important role in cancer pathogenesis. Although LSD2 histone demethylase has already been reported as an E3 ubiquitin ligase in lung cancer cells, we identified XIAP as the main E3 ubiquitin ligase in colon cancer cells. Interestingly, OGT catalyzes the O-GlcNAc modification of XIAP at serine 406 and this modification is required for the E3 ubiquitin ligase activity of XIAP toward specifically OGT. Moreover, O-GlcNAcylation of XIAP suppresses colon cancer cell growth and invasion by promoting the proteasomal degradation of OGT. Therefore, our findings regarding the reciprocal regulation of OGT and XIAP provide a novel molecular mechanism for controlling cancer growth and invasion regulated by OGT and O-GlcNAc modification.

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“…XIAP has been found to be a ubiquitin E3 ligase for Mdm2 to promote its degradation (25). It is reported that the XIAP RING domain controls the protein stability of Cdc42 through directly conjugating polyubiquitin chains to the lysine 166 of Cdc42 (26). XIAP could also ubiquitinate a highly conserved Lys residue in adenylyl cyclase isoforms and thereby accelerate their endocytosis and degradation (27).…”

Section: Discussionmentioning

confidence: 99%

The RING domain in the anti-apoptotic protein XIAP stabilizes c-Myc protein and preserves anchorage-independent growth of bladder cancer cells

Jiang

Huang

Liao

et al. 2019

Journal of Biological Chemistry

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Edited by Eric R. Fearon X-linkedinhibitorofapoptosisprotein(XIAP)suppressesapoptosis and plays key roles in the development, growth, migration, and invasion of cancer cells. Therefore, XIAP has recently attracted much attention as a potential antineoplastic therapeutic target, requiring elucidation of the molecular mechanisms underlying its biological activities. Here, using shRNA-mediated gene silencing, immunoblotting, quantitative RT-PCR, anchorage-independent growth assay, and invasive assay, we found that XIAP's RING domain, but not its BIR domain, is crucial for XIAP-mediated up-regulation of c-Myc protein expression in human bladder cancer (BC) cells. Mechanistically, we observed that the RING domain stabilizes c-Myc by inhibiting its phosphorylation at Thr-58 and that this inhibition is due to activated ERK1/2-mediated phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) at Ser-9. Functional studies further revealed that c-Myc protein promotes anchorage-independent growth and invasion stimulated by the XIAP RING domain in human BC cells. Collectively, the findings in our study uncover that the RING domain of XIAP supports c-Myc protein stability, providing insight into the molecular mechanism and role of c-Myc overexpression in cancer progression. Our observations support the notion of targeting XIAP's RING domain and c-Myc in cancer therapy. . 4 The abbreviations used are: BC, bladder cancer; XIAP, X-linked inhibitor of apoptosis protein; IAP, inhibitor of apoptosis; CHX, cycloheximide; GSK, glycogen synthase kinase; BIR, baculoviral IAP repeat; MEF, mouse embryo fibroblast; DN, dominant negative; FBS, fetal bovine serum.Figure 4. XIAP RING domain activated ERK1/2 and in turn mediated the phosphorylation of GSK-3␤ at Ser-9. A, the cell extracts from the indicated transfectants were subjected to Western blotting to detect the expression levels of the indicated proteins. GAPDH was used as the protein-loading control. B and C, cell extracts from WT versus ⌬RING MEFs (B) and ⌬RING versus ⌬RING/GFP-RING MEFs (C) were subjected to Western blotting to detect the expression levels of the indicated proteins. GAPDH was used as the protein-loading control. D-G, DN-ERK2 was overexpressed in shXIAP78/⌬BIR cells, and the stable transfectants were then subjected to Western blotting for determination of the expression of the indicated proteins. GAPDH was used as the protein-loading control. H, lysates from WT and ⌬XIAP HCT116 cells were co-immunoprecipitated with anti-XIAP antibody, and immunoprecipitates were then subjected to Western blotting for determination of c-Myc protein. *, significant difference as compared with control transfectant (p Ͻ 0.05). #, significant difference as compared with vector transfectant (p Ͻ 0.05). Error bars, S.D. XIAP RING domain stabilization of c-Myc J. Biol. Chem. (2019) 294(15) 5935-5944 5939 by guest on July 10, 2020 http://www.jbc.org/ Downloaded from Figure 5. XIAP RING domain was required for preserving the anchorage-independent growth and invasion abilities of BC cells. A-D, ...

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Ubiquitin-dependent regulation of Cdc42 by XIAP

Cited by 24 publications

References 25 publications

Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F‐box protein subunit

Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion

The RING domain in the anti-apoptotic protein XIAP stabilizes c-Myc protein and preserves anchorage-independent growth of bladder cancer cells

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