Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

Yu, Jiangtian; Zhao, Haitao; Zhang, Yan; Liu, Yun‐Cai; Yao, Libo; Li, Xia

doi:10.1016/j.febslet.2014.03.003

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…Cbl protein-mediated ubiquitination can target activated RTK for degradation, either by facilitating endocytic sorting into lysosomes or by promoting proteasomal degradation (38). In a previous study, Cbl-b was experimentally shown to function as a negative regulator in the DDR2 by promoting the ubiquitination and degradation of DDR2 (22). All three members of the Cbl family of proteins share a highly homologous N-terminal tyrosine kinase binding region, which serves as the structural platform for binding to phospho-tyrosine residues (39).…”

Section: Discussionmentioning

confidence: 99%

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Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

Terashima

Togashi

Sato

et al. 2016

Clinical Cancer Research

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Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets.Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro.Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growthsuppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor.Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen.

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Section: Discussionmentioning

confidence: 99%

“…As previously reported, Cbl-b, a family of E3 ubiquitin ligases, interacts with DDR2 and promotes its ubiquitination, resulting in its degradation (22). We next examined the interaction of DDR2 with Cbl-b using immunoprecipitation.…”

Section: Ddr2 Protein Harboring the E655k Mutation Is Sensitive To Thmentioning

confidence: 96%

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

Terashima

Togashi

Sato

et al. 2016

Clinical Cancer Research

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“…Moreover, metalloproteinases are enzymes that mediate photoaging and tissue remodeling 46 . Some metalloproteinases like MMP13 are negatively regulated by Cbl-b 47 . UVB-irradiated Cbl-b −/− mice had an increase of MMP12 expression in cells of the epidermis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cbl-b deficiency provides protection against UVB-induced skin damage by modulating inflammatory gene signature

et al. 2018

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Exposure of skin to ultraviolet (UV) radiation induces DNA damage, inflammation, and immune suppression that ultimately lead to skin cancer. However, some of the pathways that regulate these events are poorly understood. We exposed mice to UVB to study its early effects in the absence of Cbl-b, a known suppressor of antitumor immune response in the skin. Cbl-b−/− mice were protected from UV-induced cell damage as shown by the lower number of cyclobutane pyrimidine dimers and sunburn cells in exposed skin compared to wild-type mice. Microarray data revealed that deficiency of Cbl-b resulted in differential expression of genes involved in apoptosis evasion, tumor suppression and cell survival in UV-exposed skin. After UVB, Cbl-b−/− mice upregulated gene expression pattern associated with regulation of epidermal cell proliferation linked to Wnt signaling mediators and enzymes that relate to cell removal and tissue remodeling like MMP12. Additionally, the skin of Cbl-b−/− mice was protected from chronic inflammatory responses and epidermal hyperplasia in a 4-weeks UVB treatment protocol. Overall, our results suggest a novel role for Cbl-b in regulating inflammation and physiologic clearance of damaged cells in response to UVB by modulating inflammatory gene signature.

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Discoidin Domain Receptor Signalling Networks

Iwai

Payne

Allam³

et al. 2016

Discoidin Domain Receptors in Health and Disease

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Ubiquitin ligase Cbl‐b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability

Cited by 4 publications

References 36 publications

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non–Small Cell Lung Cancer: Double-Edged Sword of DDR2

Cbl-b deficiency provides protection against UVB-induced skin damage by modulating inflammatory gene signature

Discoidin Domain Receptor Signalling Networks

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