Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
J Biol Chem
; 284(9): 5582-91, 2009 Feb 27.
Article
in En
| MEDLINE
| ID: mdl-19098003
ABSTRACT
Cancer drugs targeting ErbB receptors, such as epidermal growth factor receptor and ErbB2, are currently in clinical use. However, the role of ErbB4 as a potential cancer drug target has remained controversial. Recently, somatic mutations altering the coding region of ErbB4 were described in patients with breast, gastric, colorectal, or non-small cell lung cancer, but the functional significance of these mutations is unknown. Here we demonstrate that 2 of 10 of the cancer-associated mutations of ErbB4 lead to loss of ErbB4 kinase activity due to disruption of functionally important structural features. Interestingly, the kinase-dead ErbB4 mutants were as efficient as wild-type ErbB4 in forming a heterodimeric neuregulin receptor with ErbB2 and promoting phosphorylation of Erk1/2 and Akt in an ErbB2 kinase-dependent manner. However, the mutant ErbB4 receptors failed to phosphorylate STAT5 and suppressed differentiation of MDA-MB-468 mammary carcinoma cells. These findings suggest that the somatic ErbB4 mutations have functional consequences and lead to selective changes in ErbB4 signaling.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Mitogen-Activated Protein Kinase 1
/
Mitogen-Activated Protein Kinase 3
/
Proto-Oncogene Proteins c-akt
/
STAT5 Transcription Factor
/
ErbB Receptors
/
Mutation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Biol Chem
Year:
2009
Document type:
Article
Affiliation country:
Finland