Back to Search
Start Over
Functional consequences of mutations in a putative Akt phosphorylation motif of B-raf in human cancers
- Source :
- Molecular Carcinogenesis. 43:59-63
- Publication Year :
- 2005
- Publisher :
- Wiley, 2005.
-
Abstract
- Mutations in the B-raf gene have been reported in a number of human cancers, including melanoma and lung cancer. More than 80% of the reported B-raf mutations were V599E; however, non-V599E mutations have been frequently found in non-small cell lung cancers as compared with melanoma. Some non-V599E mutations have been found surrounding Thr439, which is thought likely to be one of the three Akt phosphorylation sites in the B-raf protein. However, as a previous report indicated that Thr439 was not phosphorylated by Akt, the functional consequences of these mutations have been unclear. Here, we examined the effects of cancer-related B-raf mutations surrounding Thr439 on the activation of the mitogen-activated protein/ extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (Erk) pathway and the transformation of NIH 3T3 fibroblasts. Among the three reported mutations (K438Q, K438T, and T439P) found in non-small cell lung carcinoma and melanoma, none elevated the activity of the MEK/Erk cascade as determined by in vitro kinase assays, immunoblots using antibody specific for phosphorylated Erk, or Elk1-dependent reporter assays. The inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt signaling by LY294002 increased the Erk activation induced by the mutant B-raf proteins, as well as by wild-type B-raf. Furthermore, the B-raf mutants did not have increased NIH 3T3-transforming activities, as determined by colony-formation assays. These results suggest that the B-raf mutations surrounding Thr439 found in human cancers are unlikely to contribute to increased oncogenic properties of B-raf.
- Subjects :
- Proto-Oncogene Proteins B-raf
MAPK/ERK pathway
Cancer Research
Amino Acid Motifs
Mutant
Protein Serine-Threonine Kinases
Biology
Cell Line
chemistry.chemical_compound
Neoplasms
Proto-Oncogene Proteins
medicine
Animals
Humans
Phosphatidylinositol
Phosphorylation
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Kinase
Melanoma
medicine.disease
Molecular biology
chemistry
Mutation
Cancer research
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 10982744 and 08991987
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- Molecular Carcinogenesis
- Accession number :
- edsair.doi.dedup.....ed4e963e699ecfeb4328542045c9d077