Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors

Philippe Soubeyran, Katarzyna Kowanetz, Iwona Szymkiewicz, Wallace Y. Langdon and Ivan Dikic ()
Additional contact information
Philippe Soubeyran: Ludwig Institute for Cancer Research, Box 595
Katarzyna Kowanetz: Ludwig Institute for Cancer Research, Box 595
Iwona Szymkiewicz: Ludwig Institute for Cancer Research, Box 595
Wallace Y. Langdon: University of Western Australia
Ivan Dikic: Ludwig Institute for Cancer Research, Box 595

Nature, 2002, vol. 416, issue 6877, 183-187

Abstract: Abstract 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 transduction1,2,3,4,5. 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 vesicles7,8,9,10) 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.

Date: 2002
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/416183a Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:416:y:2002:i:6877:d:10.1038_416183a

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/416183a

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().