CIKS, a connection to IκB kinase and stress-activated protein kinase

Leonardi, Antonio; Chariot, Alain; Claudio, Estefanı́a; Cunningham, Kirk; Siebenlist, Ulrich

doi:10.1073/pnas.190245697

Cited by 149 publications

(157 citation statements)

References 51 publications

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“…Kinase assays in transfected cells were carried out as described. 27,42 IPs involving ectopically expressed or endogenous proteins were carried out as described. 40,43 For the detection of endogenous polyubiquitinated forms of HPIP (Figure 4h), MCF7 cells were pretreated with MG132.…”

Section: Methodsmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...

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Section: Methodsmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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“…LPS was purchased from Sigma-Aldrich. CpG DNA (oligonucleotide 1668) was synthesized by Invitrogen (28). Pam 2 CSK 4 was purchased from InvivoGen.…”

Section: Mice and Reagentsmentioning

confidence: 99%

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

Ori

Kato

Sanjo

et al. 2013

The Journal of Immunology

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Polyubiquitination of proteins plays a critical role in the activation of immune cells. K63-linked polyubiquitin-binding proteins TGF-β–activated kinase 1 (TAK1)–binding protein (TAB)2 and TAB3 are implicated in NF-κB signaling via TAK1 activation. However, TAB2 alone is dispensable for NF-κB activation in embryonic fibroblasts, and the functional roles of TAB2 and TAB3 in immune cells has yet to be clarified. In this study, we demonstrate that TAB2 and TAB3 are essential for B cell activation leading to Ag-specific Ab responses, as well as B-1 and marginal zone B cell development. TAB2 and TAB3 are critical for the activation of MAPKs, especially ERK, but not NF-κB, in response to TLR and CD40 stimulation in B cells. Surprisingly, TAB2 and TAB3 are dispensable for TAK1 activation in B cells, indicating that TAB2 and TAB3 activate MAPKs via a pathway independent of TAK1. In contrast to B cells, macrophages lacking TAB2 and TAB3 did not show any defects in the cytokine production and the signaling pathway in response to TLR stimulation. Furthermore, TAB2 and TAB3 were dispensable for TNF-induced cytokine production in embryonic fibroblasts. Thus, TAB2- and TAB3-mediated K63-linked polyubiquitin recognition controls B cell activation via MAPKs, but not the TAK1/NF-κB axis.

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“…Previously, we reported on the identification of one NEMO/IKK␥-interacting protein identified in this way and termed CIKS (connection to IKK and SAPK/JNK) (22) (also known as Act-1 (23)). Here we describe the identification of an additional NEMO/IKK␥-interacting protein, termed TANK (TRAF family member-associated NF-B activator).…”

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confidence: 99%

Association of the Adaptor TANK with the IκB Kinase (IKK) Regulator NEMO Connects IKK Complexes with IKKε and TBK1 Kinases

Chariot¹,

Leonardi²,

Muller³

et al. 2002

Journal of Biological Chemistry

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CIKS, a connection to IκB kinase and stress-activated protein kinase

Cited by 149 publications

References 51 publications

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

Essential Roles of K63-Linked Polyubiquitin-Binding Proteins TAB2 and TAB3 in B Cell Activation via MAPKs

Association of the Adaptor TANK with the IκB Kinase (IKK) Regulator NEMO Connects IKK Complexes with IKKε and TBK1 Kinases

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