Premium
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation
Author(s) -
Haglund Kaisa,
Schmidt Mirko H H,
Wong Esther Sook Miin,
Guy Graeme R,
Dikic Ivan
Publication year - 2005
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.7400453
Subject(s) - downregulation and upregulation , microbiology and biotechnology , epidermal growth factor , epidermal growth factor receptor , interface (matter) , growth factor receptor , receptor , chemistry , business , biology , signal transduction , biochemistry , gene , pulmonary surfactant , gibbs isotherm
The ubiquitin ligase Cbl mediates ubiquitination of activated receptor tyrosine kinases (RTKs) and interacts with endocytic scaffold complexes, including CIN85/endophilins, to facilitate RTK endocytosis and degradation. Several mechanisms regulate the functions of Cbl to ensure the fine‐tuning of RTK signalling and cellular homeostasis. One regulatory mechanism involves the binding of Cbl to Sprouty2, which sequesters Cbl away from activated epidermal growth factor receptors (EGFRs). Here, we show that Sprouty2 associates with CIN85 and acts at the interface between Cbl and CIN85 to inhibit EGFR downregulation. The CIN85 SH3 domains A and C bind specifically to proline–arginine motifs present in Sprouty2. Intact association between Sprouty2, Cbl and CIN85 is required for inhibition of EGFR endocytosis as well as EGF‐induced differentiation of PC12 cells. Moreover, Sprouty4, which lacks CIN85‐binding sites, does not inhibit EGFR downregulation, providing a molecular explanation for functional differences between Sprouty isoforms. Sprouty2 therefore acts as an inducible inhibitor of EGFR downregulation by targeting both the Cbl and CIN85 pathways.