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Regulation of Protein Kinase B Tyrosine Phosphorylation by Thyroid-Specific Oncogenic RET/PTC Kinases
- Source :
- Molecular Endocrinology. 19:2748-2759
- Publication Year :
- 2005
- Publisher :
- The Endocrine Society, 2005.
-
Abstract
- Papillary thyroid carcinoma (PTC) is a heterogenous disorder characterized by unique gene rearrangements and gene mutations that activate signaling pathways responsible for cellular transformation, survival, and antiapoptosis. Activation of protein kinase B (PKB) and its downstream signaling pathways appears to be an important event in thyroid tumorigenesis. In this study, we found that the thyroid-specific oncogenic RET/PTC tyrosine kinase is able to phosphorylate PKB in vitro and in vivo. RET/PTC-transfected cells showed tyrosine phosphorylation of endogenous and exogenous PKB, which was independent of phosphorylation of T308 and S473 regulated by the upstream kinases phosphoinositide-dependent kinase-1 and -2, respectively. The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity. The activation of PKB by RET/PTC blocked the activity of the forkhead transcription factor, FKHRL1, but a Y315F mutant of PKB failed to inhibit FKHRL1 activity. In summary, these observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis.
- Subjects :
- Cytoplasm
endocrine system
endocrine system diseases
Thyroid Gland
Protein tyrosine phosphatase
SH2 domain
Receptor tyrosine kinase
MAP2K7
chemistry.chemical_compound
Endocrinology
Animals
Humans
Thyroid Neoplasms
Phosphorylation
Molecular Biology
Cells, Cultured
biology
Akt/PKB signaling pathway
Forkhead Box Protein O3
Proto-Oncogene Proteins c-ret
Forkhead Transcription Factors
Tyrosine phosphorylation
General Medicine
Carcinoma, Papillary
chemistry
biology.protein
Cancer research
Tyrosine
Proto-Oncogene Proteins c-akt
Tyrosine kinase
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 19449917 and 08888809
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Endocrinology
- Accession number :
- edsair.doi.dedup.....db2518a51d756d428dfd59ae2bb0aee0