Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity

Min, Xiao; Zhang, Xiaohan; Sun, Ningning; Acharya, Srijan; Kim, Kyeong-Man

doi:10.1016/j.bcp.2019.113675

Cited by 17 publications

(23 citation statements)

References 63 publications

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“…MDM2 is well known as an E3 ubiquitin-protein ligase for tumor-suppressor p53. It has also been found to mediate the ubiquitination of many other substrates such as Rb [ 27 ], ACE2 [ 19 ], HDAC1 [ 18 ], PKCβII [ 28 ], and PPARα [ 25 ], leading to their degradation by the proteasome. As expected, we find that RXRβ is a newly discovered substrate of MDM2.…”

Section: Discussionmentioning

confidence: 99%

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

Zhang

Cao

et al. 2022

IJMS

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A novel function of retinoid X receptor beta (RXRβ) in endothelial cells has been reported by us during the formation of atherosclerosis. Here, we extended the study to explore the cellular mechanisms of RXRβ protein stability regulation. In this study, we discovered that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RXRβ for degradation. The result showed that MDM2 directly interacted with and regulated RXRβ protein stability. MDM2 promoted RXRβ poly-ubiquitination and degradation by proteasomes. Moreover, mutated MDM2 RING domain (C464A) or treatment with an MDM2 inhibitor targeting the RING domain of MDM2 lost the ability of MDM2 to regulate RXRβ protein expression and ubiquitination. Furthermore, treatment with MDM2 inhibitor alleviated oxidized low-density lipoprotein-induced mitochondrial damage, activation of TLR9/NF-κB and NLRP3/caspase-1 pathway and production of pro-inflammatory cytokines in endothelial cells. However, all these beneficial effects were reduced by the transfection of RXRβ siRNA. Moreover, pharmacological inhibition of MDM2 attenuated the development of atherosclerosis and reversed mitochondrial damage and related inflammation in the atherosclerotic process in LDLr-/- mice, along with the increased RXRβ protein expression in the aorta. Therefore, our study uncovers a previously unknown ubiquitination pathway and suggests MDM2-mediated RXRβ ubiquitination as a new therapeutic target in atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

Zhang

Cao

et al. 2022

IJMS

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“…Various E3 ligases have been proposed to drive PKC ubiquitination and proteasomal degradation in different contexts, including RINCK, LUBAC and MDM2 [45][46][47] .…”

Section: [H2] Turning Pkcs Offmentioning

confidence: 99%

Equivocal, explicit and emergent actions of PKC isoforms in cancer

et al. 2020

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The maturing mutational landscape of cancer genomes, the development and application of clinical interventions, and evolving insights into tumour-associated functions, reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancerassociated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this eco-system, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but the when and how is not obvious. [H1] IntroductionThe protein kinase C (PKC) family of serine/threonine protein kinases, comprising the 'classical' PKC (cPKC), 'novel' PKC (nPKC), 'atypical' PKC (aPKC) and PKN

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“…Along with phosphorylation, a recent study has shown that PKCβII is also regulated through Mdm2-mediated ubiquitination ( Min et al, 2019 ). In addition to proteasomal degradation of the target protein, ubiquitination regulates various cellular functions, such as gene expression, cell signaling, and intracellular trafficking ( Miranda & Sorkin, 2007 ; Komander & Rape, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to proteasomal degradation of the target protein, ubiquitination regulates various cellular functions, such as gene expression, cell signaling, and intracellular trafficking ( Miranda & Sorkin, 2007 ; Komander & Rape, 2012 ). Similarly, Mdm2-mediated ubiquitination of PKCβII is known to be responsible for the down-regulation and activation of PKCβII, as determined by its translocation to the plasma membrane ( Min et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…The association between actin filament and clathrin-mediated endocytosis (CME) has long been proposed ( Salisbury et al, 1980 ): F-actin dynamics are required for multiple stages of clathrin-coated vesicle formation ( Yarar et al, 2005 ), and actin assembly generally precedes dynamin 2 recruitment during the late phases of CME ( Grassart et al, 2014 ). In addition, it has been shown that both actin and clathrin are involved in the recruitment of PKCβII to the plasma membrane ( Blobe et al, 1996 ; Min et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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PKCβII activation requires nuclear trafficking for phosphorylation and Mdm2-mediated ubiquitination

et al. 2023

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PKCβII, a conventional PKC family member, plays critical roles in the regulation of a variety of cellular functions. Here, we employed loss-of-function approaches and mutants of PKCβII with altered phosphorylation and protein interaction behaviors to identify the cellular mechanisms underlying the activation of PKCβII. Our results show that 3-phosphoinositide–dependent protein kinase-1 (PDK1)–mediated constitutive phosphorylation of PKCβII at the activation loop (T500) is required for phorbol ester–induced nuclear entry and subsequent Mdm2-mediated ubiquitination of PKCβII, whereas ubiquitination of PKCβII is required for the PDK1-mediated inducible phosphorylation of PKCβII at T500 in the nucleus. After moving out of the nucleus, PKCβII interacts with actin, undergoes inducible mTORC2-mediated phosphorylation at the turn motif (T641), interacts with clathrin, and then translocates to the plasma membrane. This overall cascade of cellular events intertwined with the phosphorylation at critical residues and Mdm2-mediated ubiquitination in the nucleus and along with interactions with actin and clathrin plays roles that encompass the core processes of PKC activation.

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Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity

Cited by 17 publications

References 63 publications

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

Equivocal, explicit and emergent actions of PKC isoforms in cancer

PKCβII activation requires nuclear trafficking for phosphorylation and Mdm2-mediated ubiquitination

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