Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin

Ohno, Ayako; Ochi, Arisa; Maita, N.; Ueji, Tatsuya; Bando, Aki; Nakao, Reiko; Hirasaka, Katsuya; Abe, Tomoki; Teshima-Kondo, Shigetada; Nemoto, Hisao; Okumura, Yuushi; Higashibata, Akira; Yano, Sachiko; Tochio, Hidehito; Nikawa, Takeshi

doi:10.1016/j.abb.2016.02.014

Cited by 7 publications

(7 citation statements)

References 21 publications

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“…High-resolution structures of the TKB domains of Cbl and Cbl-b are nearly identical (for example, Protein Data Bank [PDB] codes: 3PFV, 3VGO, and 3ZNI; see also Ohno et al. , 2016 ) and do not provide clues to explain the different efficiency and/or strength of Cbl and Cbl-b interactions with the pY1045 motif observed in our experiments.…”

Section: Resultsmentioning

confidence: 77%

Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes

Pinilla-Macua,

Sorkin

2023

MBoC

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Highly homologous E3 ubiquitin ligases, Cbl and Cbl-b, mediate ubiquitination of EGF receptor (EGFR), leading to its endocytosis and lysosomal degradation. Cbl and Cbl-b, are thought to function in a redundant fashion by binding directly to phosphorylated Y1045 (pY1045) of EGFR and indirectly via the Grb2 adaptor. Unexpectedly, we found that inducible expression of Cbl or Cbl-b mutants lacking the E3 ligase activity but fully capable of EGFR binding does not significantly affect EGFR ubiquitination and endocytosis in human oral squamous cell carcinoma (HSC3) cells which endogenously express Cbl-b at a relatively high level. Each endogenous Cbl species remained associated with ligand-activated EGFR in the presence of an overexpressed counterpart species or its mutant, although Cbl-b overexpression partially decreased Cbl association with EGFR. Binding to pY1045 was the preferential mode for Cbl-b:EGFR interaction, whereas Cbl relied mainly on the Grb2-dependent mechanism. Overexpression of the E3-dead mutant of Cbl-b slowed down EGF-induced degradation of active EGFR, while this mutant and a similar mutant of Cbl did not significantly affect MAPK/ERK1/2 activity. EGF-guided chemotaxis migration of HSC3 cells was diminished by overexpression of the E3-dead Cbl-b mutant but was not significantly affected by the E3-dead Cbl mutant. By contrast, the inhibitory effect of the same Cbl mutant on the migration of OSC-19 cells expressing low Cbl-b levels was substantially stronger than that of the Cbl-b mutant. Altogether, our data demonstrate that Cbl and Cbl-b may operate independently through different modes of EGFR binding to jointly control receptor ubiquitination, endocytic trafficking and signaling.

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Section: Resultsmentioning

confidence: 77%

Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes

Pinilla-Macua,

Sorkin

2023

MBoC

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“…44 As a RF ubiquitin ligase, the biological significance of CBLB enzymatic activity is a rapidly evolving area of research, with the discovery of its role in immunomodulation of the innate immune system published in 2014. 7,8,[45][46][47][48][49] This research activity highlights the need for small-molecule modulators of CBLB activity that can be used to better understand both the biology of this target in a research setting as well as those that can be translated into a clinical setting to improve disease outcomes. The experiments described in this article are the first published cell-free screen for modulators of CBLB enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Two groups have reported peptidomimetic compounds that bind to the TKB domain of either CBL or CBLB, and block interaction with a specific substrate. 36,48,[51][52][53] These compounds are not catalytic inhibitors of E3 activity but rather allosteric agents that prevent specific substrates from being targeted by CBL or CBLB. Similarly to substrate peptidomimetics, Wu et al developed modified peptides based on the structure of the CBL RF interface with the E2 UbcH7.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors

et al. 2021

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“…The active site of casitas B-lineage lymphoma-b (Cbl-b), which is a ubiquitin ligase, is competitively blocked by a specific oligopeptide known as Cblin. Administration of Cblin suppresses IRS1 ubiquitination, prevents muscle atrophy, and retains normal insulin signals for muscle maintenance (18,19). Interestingly, glycinin, which is contained in 40% of SPI, possesses a sequence similar to the inhibitory peptide sequence of Cblin, and a 20% glycinin diet prevents muscle atrophy (7,12).…”

Section: Discussionmentioning

confidence: 99%

A Diet Including Red Bell Pepper Juice and Soy Protein Suppress Physiological Markers of Muscle Atrophy in Mice

Tachibana

Fukao²,

Irie

et al. 2020

J Nutr Sci Vitaminol

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Although muscle atrophy can be caused by disuse and lifestyle-related syndromes, it may be possible to prevent this condition through dietary intervention. We hypothesized that a diet including red bell pepper juice (RBPJ) and soy protein isolate (SPI) would prevent muscle atrophy. Accordingly, an experimental diet containing RBPJ and/or SPI was administered for 18 d to normal C57BL/6J mice. The control group was administered a casein diet. Four days before the end of the test period, denervation-induced muscle atrophy and/or sham operation were performed. Anterior tibialis muscle samples were then obtained to assess muscle degradation and perform metabolome analysis. Under the denervation condition, the 20% SPI diet did not alter the mRNA expression levels of muscle atrophy marker genes compared with the 20% casein group. Although the diet comprising RBPJ and 20% casein did not prevent muscle atrophy compared with the control group, the diet containing RBPJ and 20% SPI did. Metabolome analysis revealed that a diet including RBPJ and SPI induced a greater than 1.5-fold change in the levels of 20 muscle atrophy-related metabolites. In particular, the level of S-adenosylmethionine, which concerned with energy metabolism and lifespan, showed a strong positive correlation with the muscle atrophy marker. These findings suggest that a diet including RBPJ and soy protein suppress gene expressions related with muscle atrophy. Further research in humans is needed to confirm whether a combination of RBPJ and SPI can indeed prevent muscle atrophy.

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Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin

Cited by 7 publications

References 21 publications

Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes

Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes

In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors

A Diet Including Red Bell Pepper Juice and Soy Protein Suppress Physiological Markers of Muscle Atrophy in Mice

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