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Updated: Jun 10, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
A Dyn2-CIN85 complex mediates degradative traffic of the EGFR by regulation of late endosomal budding
Barbara Schroeder1, Shaun G Weller, Jing Chen
1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Abstract:
The epidermal growth factor receptor (EGFR) is over-expressed in a variety of human cancers. Downstream signalling of this receptor is tightly regulated both spatially and temporally by controlling its internalization and subsequent degradation. Internalization of the EGFR requires dynamin 2 (Dyn2), a large GTPase that deforms lipid bilayers, leading to vesicle scission. The adaptor protein CIN85 (cbl-interacting protein of 85 kDa), which has been proposed to indirectly link the EGFR to the endocytic machinery at the plasma membrane, is also thought to be involved in receptor internalization. Here, we report a novel and direct interaction between Dyn2 and CIN85 that is induced by EGFR stimulation and, most surprisingly, occurs late in the endocytic process. Importantly, disruption of the CIN85-Dyn2 interaction results in accumulation of internalized EGFR in late endosomes that become aberrantly elongated into distended tubules. Consistent with the accumulation of this receptor is a sustention of downstream signalling cascades. These findings provide novel insights into a previously unknown protein complex that can regulate EGFR traffic at very late stages of the endocytic pathway.
Insights
A novel interaction between CIN85 and dynamin 2 (Dyn2) regulates epidermal growth factor receptor (EGFR) internalization. Disrupting this complex causes EGFR accumulation and sustained signaling, revealing a new regulatory mechanism in endocytosis.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR) overexpression is common in human cancers.
- EGFR signaling is regulated by its internalization and degradation.
- Dynamin 2 (Dyn2) and CIN85 are implicated in EGFR internalization.
Purpose of the Study:
- To investigate the interaction between Dyn2 and CIN85 in EGFR trafficking.
- To elucidate the role of this interaction in the endocytic pathway.
Main Methods:
- Studied the interaction between Dyn2 and CIN85 upon EGFR stimulation.
- Investigated the consequences of disrupting the CIN85-Dyn2 interaction on EGFR localization and signaling.
Main Results:
- Identified a novel, direct interaction between Dyn2 and CIN85, occurring late in endocytosis upon EGFR stimulation.
- Disruption of the CIN85-Dyn2 interaction led to accumulation of internalized EGFR in abnormally shaped late endosomes.
- EGFR accumulation resulted in sustained downstream signaling cascades.
Conclusions:
- Discovered a previously unknown protein complex involving CIN85 and Dyn2 that regulates late-stage EGFR trafficking.
- This complex plays a critical role in controlling EGFR degradation and downstream signaling.
- Findings offer new insights into cancer-related signaling pathways.
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