A Dyn2-CIN85 complex mediates degradative traffic of the EGFR by regulation of late endosomal budding.
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.
Schroeder
Barbara
B
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Weller
Shaun G
SG
Chen
Jing
J
Billadeau
Daniel
D
McNiven
Mark A
MA
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D034285:Dynamin II / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D034741:RNA, Small Interfering; C433810:SH3KBP1 protein, human; D000090802:rab7 GTP-Binding Proteins; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins; D034285:Dynamin II