Dataset Information

Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

ABSTRACT: Addition of ubiquitin or ubiquitin chains to target proteins leads to their mono- or polyubiquitination, respectively. Whereas polyubiquitination targets proteins for degradation, monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Cbl proteins are major ubiquitin ligases that promote ligand-dependent polyubiquitination and degradation of receptor tyrosine kinases. They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling receptor endocytosis. Here we show that the adaptor protein CIN85 and its homologue CMS are monoubiquitinated by Cbl/Cbl-b after epidermal growth factor (EGF) stimulation. Monoubiquitination of CIN85 required direct interactions between CIN85 and Cbl, the intact RING finger domain of Cbl and a ubiquitin acceptor site present in the carboxyl terminus of CIN85. Cbl-b and monoubiquitinated CIN85 are found in the complex with polyubiquitinated EGF receptors during prolonged EGF stimulation and are degraded together in the lysosome. Dominant interfering forms of CIN85, which have been shown previously to delay EGF receptor degradation, were also impaired in their monoubiquitination. Thus, our data demonstrate that Cbl/Cbl-b can mediate polyubiquitination of cargo as well as monoubiquitination of CIN85 to control endosomal sorting and degradation of receptor tyrosine kinases.

SUBMITTER: Haglund K

PROVIDER: S-EPMC129420 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

Haglund Kaisa K Shimokawa Noriaki N Szymkiewicz Iwona I Dikic Ivan I

Proceedings of the National Academy of Sciences of the United States of America 20020906 19

Addition of ubiquitin or ubiquitin chains to target proteins leads to their mono- or polyubiquitination, respectively. Whereas polyubiquitination targets proteins for degradation, monoubiquitination is thought to regulate receptor internalization and endosomal sorting. Cbl proteins are major ubiquitin ligases that promote ligand-dependent polyubiquitination and degradation of receptor tyrosine kinases. They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling r ...[more]

PMID: 12218189

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Project description:ERK activation is enhanced by the scaffolding proteins KSR and MP1, localized near the cell membrane and late endosomes respectively, but little is known about their dynamic interplay. We develop here a mathematical model with ordinary differential equations to describe the dynamic activation of EGFR-ERK signaling under a conventional pathway without scaffolds, a KSR-scaffolded pathway, and an MP1-scaffolded pathway, and their impacts were examined under the influence of the endosomal regulators, Cbl-CIN85 and Endophilin A1. This new integrated model, validated against experimental results and computational constraints, shows that changes of ERK activation and EGFR endocytosis in response to EGF concentrations (i.e ligand sensitivity) depend on these scaffold proteins and regulators. The KSR-scaffolded and the conventional pathways act synergistically and are sensitive to EGF stimulation. When the KSR level is high, the sensitivity of ERK activation from this combined pathway remains low when Cbl-CIN85 level is low. But, such sensitivity can be increased with increasing levels of Endophilin if Cbl-CIN85 level becomes high. However, reduced KSR levels already present high sensitivity independent of Endophilin levels. In contrast, ERK activation by MP1 is additive to that of KSR but it shows little ligand-sensitivity under high levels of EGF. This can be partly reversed by increasing level of Endophilin while keeping Cbl-CIN85 level low. Further analyses showed that high levels of KSR affect ligand-sensitivity of EGFR endocytosis whereas MP1 ensures the robustness of endosomal ERK activation. These simulations constitute a multi-dimensional exploration of how EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1. Together, these results provide a detailed and quantitative demonstration of how regulators and scaffolds can collaborate to fine-tune the ligand-dependent sensitivity of EGFR endocytosis and ERK activation which could underlie differences during normal physiology, disease states and drug responses.

Dataset Information

Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

Publications

Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors.

Similar Datasets

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