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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3-Phosphoinositide-Dependent Protein Kinases
-
Amino Acid Sequence
-
Animals
-
CHO Cells
-
Carcinoma, Papillary / enzymology
-
Carcinoma, Papillary / metabolism
-
Cricetinae
-
Enzyme Inhibitors / pharmacology
-
Fibroblasts / metabolism
-
Humans
-
Mice
-
Molecular Sequence Data
-
Nuclear Receptor Coactivators
-
Oncogene Proteins / genetics
-
Oncogene Proteins / metabolism
-
Oncogene Proteins, Fusion / genetics
-
Oncogene Proteins, Fusion / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism*
-
Phosphoinositide-3 Kinase Inhibitors
-
Phosphorylation
-
Protein Serine-Threonine Kinases / metabolism*
-
Protein-Tyrosine Kinases
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-akt
-
Proto-Oncogene Proteins c-ret
-
Receptor Protein-Tyrosine Kinases / genetics
-
Receptor Protein-Tyrosine Kinases / metabolism*
-
Signal Transduction
-
Thyroid Neoplasms / enzymology
-
Thyroid Neoplasms / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Transcriptional Activation
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
-
Tyrosine / metabolism
-
src-Family Kinases / genetics
-
src-Family Kinases / metabolism
Substances
-
Enzyme Inhibitors
-
NCOA4 protein, human
-
Nuclear Receptor Coactivators
-
Oncogene Proteins
-
Oncogene Proteins, Fusion
-
Phosphoinositide-3 Kinase Inhibitors
-
Proto-Oncogene Proteins
-
Transcription Factors
-
Tumor Suppressor Protein p53
-
Tyrosine
-
Protein-Tyrosine Kinases
-
Proto-Oncogene Proteins c-ret
-
Receptor Protein-Tyrosine Kinases
-
Ret protein, mouse
-
ret-PTC fusion oncoproteins, human
-
src-Family Kinases
-
3-Phosphoinositide-Dependent Protein Kinases
-
PDPK1 protein, human
-
Pdpk1 protein, mouse
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt