Premium
RASopathy‐Associated CBL Germline Mutations Cause Aberrant Ubiquitylation and Trafficking of EGFR
Author(s) -
Brand Kristina,
Kentsch Hendrik,
Glashoff Christina,
Rosenberger Georg
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22682
Subject(s) - noonan syndrome , biology , ubiquitin ligase , internalization , cancer research , ubiquitin , mutation , mapk/erk pathway , epidermal growth factor receptor , germline mutation , signal transduction , microbiology and biotechnology , genetics , receptor , gene
Noonan syndrome, a congenital disorder comprising a characteristic face, short stature, heart defects, learning difficulties, and a predisposition to malignancies, is caused by heterozygous germline mutations in genes encoding components of RAS‐MAPK signaling pathways. Mutations in the CBL tumor suppressor gene have been reported in patients with a Noonan syndrome‐like phenotype. CBL encodes a multivalent adaptor protein with ubiquitin ligase activity, which promotes ubiquitylation and vesicle‐mediated internalization and degradation of the epidermal growth factor (EGF) receptor (EGFR). We investigated the functional consequences of disease‐associated CBL amino acid changes p.K382E, p.D390Y, and p.R420Q on ligand‐induced EGFR trafficking. Expression of CBL K382E , CBL D390Y , or CBL R420Q in COS‐7 cells resulted in increased levels of surface EGFR and reduced amounts of intracellular EGFR; both consequences indicate ineffective EGFR internalization. Accordingly, receptor‐mediated uptake of EGF was decreased. Furthermore, the p.K382E, p.D390Y, and p.R420Q lesions impaired CBL‐mediated EGFR ubiquitylation and degradation. Together, these data indicate that pathogenic CBL mutations severely affect vesicle‐based EGFR trafficking. Since we detected enhanced ERK phosphorylation in cells expressing mutant CBL, we conclude that aberrant EGFR trafficking contributes to augmented RAS‐MAPK signaling, the common trait of Noonan syndrome and related RASopathies. Thus, our data suggest that EGFR trafficking is a novel disease‐relevant regulatory level in the RASopathy network.