Details
- Autor(en) / Beteiligte
- Titel
- Intersectin‐s interaction with DENND2B facilitates recycling of epidermal growth factor receptor
- Ist Teil von
- EMBO reports, 2017-12, Vol.18 (12), p.2119-2130
- Ort / Verlag
- England: Blackwell Publishing Ltd
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Epidermal growth factor (EGF) activates the EGF receptor (EGFR) and stimulates its internalization and trafficking to lysosomes for degradation. However, a percentage of EGFR undergoes ligand‐independent endocytosis and is rapidly recycled back to the plasma membrane. Importantly, alterations in EGFR recycling are a common hallmark of cancer, and yet, our understanding of the machineries controlling the fate of endocytosed EGFR is incomplete. Intersectin‐s is a multi‐domain adaptor protein that is required for internalization of EGFR. Here, we discover that intersectin‐s binds DENND2B, a guanine nucleotide exchange factor for the exocytic GTPase Rab13, and this interaction promotes recycling of ligand‐free EGFR to the cell surface. Intriguingly, upon EGF treatment, DENND2B is phosphorylated by protein kinase D and dissociates from intersectin‐s, allowing for receptor targeting to degradation. Our study thus reveals a novel mechanism controlling the fate of internalized EGFR with important implications for cancer. Synopsis Whether EGFR is recycled or degraded is critical for growth signalling in cancer. The endocytic adaptor intersectin binds the Rab13 exchange factor DENND2B and drives unliganded EGFR into a recycling pathway, while EGF disrupts this interaction and targets EGFR for degradation. In the absence of EGF, DENND2B binds ITSN‐s driving internalized EGFR into a recycling pathway. EGF promotes DENND2B phosphorylation by protein kinase D, disrupting the interaction with ITSN‐s. In the absence of ITSN‐s interaction with DENND2B, EGFR is targeted for degradation. Whether EGFR is recycled or degraded is critical for growth signalling in cancer. The endocytic adaptor intersectin binds the Rab13 exchange factor DENND2B and drives unliganded EGFR into a recycling pathway, while EGF disrupts this interaction and targets EGFR for degradation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1469-221XeISSN: 1469-3178DOI: 10.15252/embr.201744034Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5709770
- Format
- –
- Schlagworte
- Adaptor Proteins, Vesicular Transport - metabolism, Cancer, Cell Membrane - metabolism, Cell surface, Degradation, DENN domain, Endocytosis, Epidermal growth factor, Epidermal Growth Factor - metabolism, Epidermal Growth Factor - pharmacology, Epidermal growth factor receptors, ErbB Receptors - drug effects, ErbB Receptors - genetics, ErbB Receptors - metabolism, exocytosis, growth signalling, Guanine, Guanine nucleotide exchange factor, Guanine Nucleotide Exchange Factors - genetics, Guanine Nucleotide Exchange Factors - metabolism, Guanosine triphosphatases, HEK293 Cells, Humans, Internalization, Intersectin, intersectin‐s, Kinases, Ligands, Lysosomes, Neoplasms - physiopathology, Phosphorylation, Protein Binding, Protein kinase, Protein Kinase C - metabolism, Protein Transport, Protein turnover, Proteins, rab GTP-Binding Proteins - metabolism, Recycling, Scientific Report, Scientific Reports, Signal Transduction, Signaling, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism