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RET/PTC (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (PDK1): an alternative phosphatidylinositol 3-kinase-independent pathway to activate PDK1
- Source :
- Molecular endocrinology (Baltimore, Md.). 17(7)
- Publication Year :
- 2003
-
Abstract
- Thyroid cancers are a leading cause of death due to endocrine malignancies. RET/PTC (rearranged in transformation/papillary thyroid carcinomas) gene rearrangements are the most frequent genetic alterations identified in papillary thyroid carcinoma. Although the oncogenic potential of RET/PTC is related to intrinsic tyrosine kinase activity, the substrates for this enzyme are yet to be identified. In this report, we show that phosphoinositide-dependent kinase 1 (PDK1), a pivotal serine/threonine kinase in growth factor-signaling pathways, is a target of RET/PTC. RET/PTC and PDK1 colocalize in the cytoplasm. RET/PTC phosphorylates a specific tyrosine (Y9) residue located in the N-terminal region of PDK1. Y9 phosphorylation of PDK1 by RET/PTC requires an intact catalytic kinase domain. The short (iso 9) and long forms (iso 51) of the RET/PTC kinases (RET/PTC1 and RET/PTC3) induce Y9 phosphorylation of PDK1. Moreover, Y9 phosphorylation of PDK1 by RET/PTC does not require phosphatidylinositol 3-kinase or Src activity. RET/PTC-induced phosphorylation of the Y9 residue results in increased PDK1 activity, decrease of cellular p53 levels, and repression of p53-dependent transactivation. In conclusion, RET/PTC-induced tyrosine phosphorylation of PDK1 may be one of the mechanisms by which it acts as an oncogenic tyrosine kinase in thyroid carcinogenesis.
- Subjects :
- Transcriptional Activation
congenital, hereditary, and neonatal diseases and abnormalities
endocrine system
animal structures
endocrine system diseases
Oncogene Proteins, Fusion
Molecular Sequence Data
Nuclear Receptor Coactivators
CHO Cells
Mitogen-activated protein kinase kinase
Biology
Protein Serine-Threonine Kinases
3-Phosphoinositide-Dependent Protein Kinases
Mice
Phosphatidylinositol 3-Kinases
Endocrinology
Cricetinae
Proto-Oncogene Proteins
Animals
Humans
Amino Acid Sequence
Thyroid Neoplasms
Enzyme Inhibitors
Phosphorylation
neoplasms
Molecular Biology
Phosphoinositide-3 Kinase Inhibitors
Oncogene Proteins
Kinase
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
General Medicine
Fibroblasts
Protein-Tyrosine Kinases
Carcinoma, Papillary
src-Family Kinases
Protein kinase domain
Cancer research
Tyrosine
Cyclin-dependent kinase 9
Tumor Suppressor Protein p53
Tyrosine kinase
Proto-Oncogene Proteins c-akt
Proto-oncogene tyrosine-protein kinase Src
Signal Transduction
Transcription Factors
Subjects
Details
- ISSN :
- 08888809
- Volume :
- 17
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Molecular endocrinology (Baltimore, Md.)
- Accession number :
- edsair.doi.dedup.....d2cac98721175955c16097f4e42f2936