Faculty Collaboration Database

Essential role of c-Cbl in amphiregulin-induced recycling and signaling of the endogenous epidermal growth factor receptor. Biochemistry 2009 Feb 24;48(7):1462-73

Date

01/29/2009

Pubmed ID

19173594

Pubmed Central ID

PMC2645952

DOI

10.1021/bi801771g

Scopus ID

2-s2.0-61749093610 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

The intracellular processing of the epidermal growth factor receptor (EGFR) induced by epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) has been studied meticulously, with the former resulting in EGFR degradation and the latter in EGFR recycling to the plasma membrane. However, little is known about how other EGF family growth factors affect the trafficking of the EGFR. Additionally, although both EGF and TGF-alpha have been shown to effectively induce initial c-Cbl (ubiquitin ligase)-mediated ubiquitination of the EGFR, limited information is available regarding the role of c-Cblin the trafficking and signaling of recycling EGFR. Thus, in this study, we investigated the roles of c-Cblin endogenous EGFR trafficking and signaling after stimulation with amphiregulin (AR). We demonstrated that a physiological concentration of AR induced recycling of the endogenous EGFR to the plasma membrane, which correlated closely with transient association of the EGFR with c-Cbl and transient EGFR ubiquitination. Most importantly, we used c-Cbl small interfering RNA (siRNA) duplexes and ac-Cbl dominant negative mutant to show that c-Cbl is critical for the efficient transition of the EGFR from early endosomes to a recycling pathway and that c-Cbl regulates the duration of extracellular signal regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) phosphorylation. These data support novel functions of c-Cbl in mediating recycling of EGF receptors to the plasma membrane, as well as in mediating the duration of activation (transient vs sustained) of ERK1/2 MAPK phosphorylation.

Author List

Baldys A, Göoz M, Morinelli TA, Lee MH, Raymond JR Jr, Luttrell LM, Raymond JR Sr

Author

John R. Raymond MD President, CEO, Professor in the President department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amphiregulin
Blotting, Western
Cell Line
EGF Family of Proteins
Endocytosis
ErbB Receptors
Fluorescent Antibody Technique
Glycoproteins
Humans
Intercellular Signaling Peptides and Proteins
Ligands
Microscopy, Confocal
Phosphorylation
Proto-Oncogene Proteins c-cbl
RNA Interference
RNA, Small Interfering
Signal Transduction
Ubiquitination