Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors.
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.
Soubeyran
Philippe
P
Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden.
Kowanetz
Katarzyna
K
Szymkiewicz
Iwona
I
Langdon
Wallace Y
WY
Dikic
Ivan
I
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008024:Ligands; D046911:Macromolecular Substances; D011233:Precipitin Tests; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D008024:Ligands; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; C107640:SH3GL2 protein, human; C433810:SH3KBP1 protein, human; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C067419:CBL protein, human