Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-κB inactivation to regulate breast cancer cell invasion

Jang, Kang Won; Lee, Kyung Hye; Kim, Soo Hyuk; Jin, Tao; Choi, Eun Young; Jeon, Hyun Ju; Kim, Eunsuk; Han, Ye; Chung, Ji Hyung

doi:10.1002/jcb.23292

Cited by 64 publications

(60 citation statements)

References 27 publications

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“…CHIP knockdown in breast cancer cells substantially elevates levels of cell invasion (47). Similarly, we observed that SKOV3 cells with CHIP knockdown exhibited increased cell invasion.…”

Section: Discussionsupporting

confidence: 71%

“…Similarly, we observed that SKOV3 cells with CHIP knockdown exhibited increased cell invasion. The mechanism of CHIP-dependent regulation of invasion is not well understood; however, it is possible that the loss of CHIP causes the accumulation of signaling proteins such as MLK3, TRAF2, Raf-1, and ErbB2, which are key regulators of invasion (47)(48)(49). The accumulation of TRAF2 in CHIP knockdown cells might also increase cell invasion by enhancing MLK3 activation (5,17).…”

Section: Discussionmentioning

confidence: 99%

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The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

Blessing

Brockman

Chadee

2014

Molecular and Cellular Biology

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Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that has regulatory roles in diverse biological processes such as proliferation, migration, differentiation, invasion, and neuronal cell apoptosis (1-9). MLK3 activates the c-Jun N-terminal kinase (JNK) and p38 MAPK signaling pathways, and in certain cellular contexts, MLK3 has a kinase-independent function in the activation of extracellular signal-regulated kinase (ERK) MAPK signaling (1, 10-12). Aberrant levels of total and/or activated MLK3 protein have been observed in ovarian and breast cancer cells in comparison to nonneoplastic ovarian and breast epithelial cells (5, 6). Moreover, a critical function for MLK3 in breast and ovarian cancer cell invasion was recently identified (5, 6). The regulation of MLK3 by phosphorylation, dimerization, and interaction with Rho GTPases has been the focus of numerous studies; however, the mechanism(s) that controls the level of total MLK3 protein in cells remains poorly understood (13-16).We previously identified that in SKOV3 ovarian cancer cells, the proinflammatory cytokines tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) induced the activation of MLK3 and that TNF-␣ also stimulated MLK3 ubiquitination (17). TNF-␣-dependent activation of MLK3 is facilitated by TNF receptor-associated factor 2 (TRAF2) and TRAF6, which interact with MLK3 and are recruited to the TNF receptor (17,18). Recently, it was demonstrated that TRAF6 promotes K63-linked polyubiquitination of MLK3 in vitro (19). Furthermore, MLK3 activation in response to IL-1␤ is dependent on TRAF6 binding and K63-linked polyubiquitination (17,19). MLK3 also undergoes K48-linked polyubiquitination; however, the role of this modification in MLK3 protein function and turnover has not been elucidated (17).MLK3 interacts with the chaperone protein Hsp90 and the cochaperone protein p50cdc37, which participate in the folding and stabilization of signaling proteins involved in proliferation, apoptosis, and survival (20, 21). The dissociation of Hsp90 from its client proteins can be triggered by specific stimuli or by exposure to Hsp90 ATPase inhibitors such as geldanamycin (GA) (22,23). Treatment of cancer cell lines with GA causes a reduction in the level of endogenous MLK3 protein and an inhibition of JNK signaling, which suggests that the Hsp90-MLK3 interaction is important for MLK3 function and stability (21,24). The disruption of Hsp90 chaperone-client interactions can lead to ubiquitination and proteasomal degradation of the client proteins via Hsp70-dependent recruitment of the carboxyl terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin ligase (20,22,23). CHIP is a Ubox E3 protein that mediates cytosolic protein polyubiquitination and targets Hsp70-bound proteins for degradation by the 26S proteasome, thereby coupling the chaperone and ubiquitin-proteasome systems (25)(26)(27)(28). In this study, we investigated the role of CHIP in the ubiquitination and degradation of MLK3 in response to GA, hea...

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“…CHIP knockdown in breast cancer cells substantially elevates levels of cell invasion (47). Similarly, we observed that SKOV3 cells with CHIP knockdown exhibited increased cell invasion.…”

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

Blessing

Brockman

Chadee

2014

Molecular and Cellular Biology

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“…Signaling through TRAF2, but not TRAF1 or TRAF3, is known to promote NF-B activity, and TRAF2 is also responsible for promoting JNK/SAPK activity, inflammation, cell migration, and chemo-and radioresistance of cancer cells (41)(42)(43)(44)(45)(46)(47). Moreover, specific depletion of TRAF2 in GB has been shown to inhibit growth and confer radiosensitization to tumor cells (48).…”

Section: Discussionmentioning

confidence: 99%

The Src Homology 3 Domain-containing Guanine Nucleotide Exchange Factor Is Overexpressed in High-grade Gliomas and Promotes Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Fibroblast Growth Factor-inducible 14-induced Cell Migration and Invasion via Tumor Necrosis Factor Receptor-associated Factor 2

Ensign

Mathews

Eschbacher

et al. 2013

Journal of Biological Chemistry

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Background: Glioblastoma is characterized by heightened cell invasion and therapeutic resistance. Results: The Src homology 3 domain-containing GEF (SGEF) promotes fibroblast growth factor-inducible 14 (Fn14) proinvasive signaling in glioblastoma via TNF receptor-associated factor 2 (TRAF2). Conclusion: SGEF is an important regulator of glioblastoma cell invasion downstream of Fn14. Significance: Therapy directed at mediators of invasion may confer increased chemotherapeutic and radiologic susceptibility in glioblastoma.

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“…C terminus of Hsp70-interacting protein (CHIP) is a U-box-dependent E3 ubiquitin ligase which is highly expressed in human striated muscle, aortic smooth muscle cells (SMCs), and endothelial cell [12]. Increasing evidence suggests that CHIP plays a critical role in the regulation of cell growth, apoptosis, neurodegeneration, invasion, SMC differentiation and cardiac fibrosis [13,14,15]. Recently, it is reported that CHIP also participates in innate immunity through TLR4 and TLR9, rather than TLR3-driven pathway.…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor-2 Ligand Peptidoglycan Upregulates Expression and Ubiquitin Ligase Activity of CHIP through JNK Pathway

Meng

Chen²,

Wang³

et al. 2013

Cell Physiol Biochem

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Background: Peptidoglycan (PGN) is a component of cell wall in Gram-positive bacteria that stimulates inflammatory responses through Toll-like receptor 2 (TLR2). The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)-interacting protein (CHIP, also known as Stub1) is a U-box-type E3 ubiquitin ligase, which plays an important role in protein quality control and inflammation through ubquitin-mediated proteasomal degradation. However, it is unclear whether TLR2 agonist PGN regulates the expression and activation of CHIP. Methods/Results: In this study, we showed that PGN significantly up-regulated the expression of CHIP in both mRNA and protein levels in RAW264.7 cells in a time-dependant manner, and the expression of CHIP induced by PGN was abolished in TLR2 knockout macrophages. No significant change in CHIP was observed after lipopolysaccharide (LPS, TLR4 agonist) and cytosine-phosphorous-guanine oligonucleotide (CpG ODN, TLR9 agonist) treatment. Moreover, PGN markedly induced the expression and activity of CHIP in macrophages, whereas this effect was attenuated by SP600125, a selective inhibitor of JNK. Conclusion: Our study for the first time demonstrates that TLR2 activation enhances the expression and activity of CHIP through JNK signaling pathway.

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Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-κB inactivation to regulate breast cancer cell invasion

Cited by 64 publications

References 27 publications

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

The E3 Ligase CHIP Mediates Ubiquitination and Degradation of Mixed-Lineage Kinase 3

Toll-Like Receptor-2 Ligand Peptidoglycan Upregulates Expression and Ubiquitin Ligase Activity of CHIP through JNK Pathway

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