The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation

Chung, Chaeuk; Yoo, Geon; Kim, Tackhoon; Lee, Dong Hoon; Lee, Choong-Sik; Rim, Hye; Park, Yeon Hee; Moon, Jae Young; Jung, Sung Soo; Kim, Ju Ock; Lee, Jae Cheol; Kim, Sun Young; Park, Hee Sun; Park, Myoungrin; Park, Dong Il; Lim, Dae‐Sik; Jang, Kang Won; Lee, Jeong Eun

doi:10.1016/j.bbrc.2016.07.111

Cited by 23 publications

(18 citation statements)

References 25 publications

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“…Apparently, Hsp90 stabilizes clients like RTKs by preventing their CHIP‐mediated ubiquitination . Consistent with the proposed specificity of Hsp90/Hsp70 to dynamic RTKs, CHIP selectively decreased the expression of oncogenic EGFR mutants of lung cancer, but not the wild‐type form of EGFR, while selectively inducing their ubiquitination and proteasomal degradation . Because specific inhibitors of Hsp90 are available, deeper understanding of the ability of Hsp90/Hsp70 to sort some RTKs for intracellular degradation may translate to effective anticancer drugs.…”

Section: Lysosomal and Proteasomal Degradation Of Preubiquitinated Rtksmentioning

confidence: 70%

Irreversible modifications of receptor tyrosine kinases

2018

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Each group of the 56 receptor tyrosine kinases (RTK) binds with one or more soluble growth factors and coordinates a vast array of cellular functions. These outcomes are tightly regulated by inducible post-translational events, such as tyrosine phosphorylation, ubiquitination, ectodomain shedding, and regulated intramembrane proteolysis. Because of the delicate balance required for appropriate RTK function, cells may become pathogenic upon dysregulation of RTKs themselves or their post-translational covalent modifications. For example, reduced ectodomain shedding and decreased ubiquitination of the cytoplasmic region, both of which enhance growth factor signals, characterize malignant cells. Whereas receptor phosphorylation and ubiquitination are reversible, proteolytic cleavage events are irreversible, and either modification might alter the subcellular localization of RTKs. Herein, we focus on ectodomain shedding by metalloproteinases (including ADAM family proteases), cleavage within the membrane or cytoplasmic regions of RTKs (by gamma-secretases and caspases, respectively), and complete receptor proteolysis in lysosomes and proteasomes. Roles of irreversible modifications in RTK signaling, pathogenesis, and pharmacology are highlighted.

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Section: Lysosomal and Proteasomal Degradation Of Preubiquitinated Rtksmentioning

confidence: 70%

Irreversible modifications of receptor tyrosine kinases

2018

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“…For this purpose, the binder moiety should be fused with a module targeting the protein to the proteasomes. Several examples of such reprogrammed E3 ubiquitin ligases have been described, based on multi-subunit RING E3 enzymes, targeting β-catenin ( Su et al, 2003 ; Liu et al, 2004 ) or mono-molecule U-box protein CHIP E3 ligase, degrading KRAS ( Ma et al, 2013 ; Pan et al, 2016 ), c-Myc ( Hatakeyama et al, 2005 ), epidermal growth factor receptor mutants ( Chung et al, 2016 ). Fusion with CHIP has several advantages over RING E3 ligases, such as broad substrate diversity and a lack of dependence on other subunits ( Portnoff et al, 2014 ).…”

Section: Strategies For Intracellular Targeting Of Antibodies Their mentioning

confidence: 99%

Targeted Intracellular Delivery of Antibodies: The State of the Art

et al. 2018

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A dominant area of antibody research is the extension of the use of this mighty experimental and therapeutic tool for the specific detection of molecules for diagnostics, visualization, and activity blocking. Despite the ability to raise antibodies against different proteins, numerous applications of antibodies in basic research fields, clinical practice, and biotechnology are restricted to permeabilized cells or extracellular antigens, such as membrane or secreted proteins. With the exception of small groups of autoantibodies, natural antibodies to intracellular targets cannot be used within living cells. This excludes the scope of a major class of intracellular targets, including some infamous cancer-associated molecules. Some of these targets are still not druggable via small molecules because of large flat contact areas and the absence of deep hydrophobic pockets in which small molecules can insert and perturb their activity. Thus, the development of technologies for the targeted intracellular delivery of antibodies, their fragments, or antibody-like molecules is extremely important. Various strategies for intracellular targeting of antibodies via protein-transduction domains or their mimics, liposomes, polymer vesicles, and viral envelopes, are reviewed in this article. The pitfalls, challenges, and perspectives of these technologies are discussed.

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“…CHIP's potential as a therapeutic target centers on its ability to promote ubiquitination and proteasomal degradation of client proteins of the Hsp90/Hsp70 based chaperone machinery (Zhou et al, 2003; Pratt et al, 2015; Chung et al, 2016). In this machinery, Hsp90 and Hsp70 bind to client proteins in their native or near native conformations to regulate many aspects of proteostasis.…”

Section: Ubiquitinating Enzymes (E3s) In Polyq Diseasesmentioning

confidence: 99%

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Nath

Lieberman

2017

Front. Mol. Neurosci.

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Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression. As a result, a vast body of research has focused on eliminating the mutant protein to broadly prevent downstream toxicity, either by silencing mutant protein expression or leveraging the endogenous protein quality control machinery. In the latter approach, a focus has been placed on four critical components of mutant protein degradation that are active in the nucleus, a key site of toxicity: disaggregation, ubiquitination, deubiquitination, and proteasomal activity. These machineries have unique functional components, but work together as a cellular defense system that can be successfully leveraged to alleviate disease phenotypes in several models of polyglutamine toxicity. This review will highlight recent advances in understanding both the potential and role of these components of the protein quality control machinery in polyglutamine disease pathophysiology.

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The E3 ubiquitin ligase CHIP selectively regulates mutant epidermal growth factor receptor by ubiquitination and degradation

Cited by 23 publications

References 25 publications

Irreversible modifications of receptor tyrosine kinases

Irreversible modifications of receptor tyrosine kinases

Targeted Intracellular Delivery of Antibodies: The State of the Art

The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

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