Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors
2002 (English)In: Nature, ISSN 0028-0836, Vol. 416, no 6877, 183-187 p.Article in journal (Refereed) Published
Cbl is a multi-adaptor protein involved in ligand-induced downregulation of receptor tyrosine kinases. It is thought that Cbl-mediated ubiquitination of active receptors is essential for receptor degradation and cessation of receptor-induced signal transduction. Here we demonstrate that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis. Cbl rapidly recruits CIN85 (Cbl-interacting protein of 85K; ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated EGF receptors, thus controlling receptor internalization. CIN85 was constitutively associated with endophilins, whereas CIN85 binding to the distal carboxy terminus of Cbl was increased on EGF stimulation. Inhibition of these interactions was sufficient to block EGF receptor internalization, delay receptor degradation and enhance EGF-induced gene transcription, without perturbing Cbl-directed receptor ubiquitination. Thus, the evolutionary divergent C terminus of Cbl uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.
Place, publisher, year, edition, pages
2002. Vol. 416, no 6877, 183-187 p.
Adaptor Proteins; Signal Transducing, Animals, CHO Cells, Carrier Proteins/genetics/*metabolism, Cell Line, Cricetinae, Down-Regulation/*drug effects, Endocytosis/drug effects, Epidermal Growth Factor/*pharmacology, Genes; Reporter/genetics, Humans, Ligands, Macromolecular Substances, Precipitin Tests, Protein Binding/drug effects, Proto-Oncogene Proteins/*metabolism, Proto-Oncogene Proteins c-cbl, Receptor; Epidermal Growth Factor/*metabolism, Ubiquitin-Protein Ligases
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-90464DOI: 10.1038/416183aPubMedID: 11894095OAI: oai:DiVA.org:uu-90464DiVA: diva2:162827
Erratum in Nature 2002 May 2 ;417(6884):102.
Doi: 10.1038/417102b2003-04-282003-04-282013-06-12Bibliographically approved