Regulation of protein kinase B tyrosine phosphorylation by thyroid-specific oncogenic RET/PTC kinases.
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.
Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku, Daejeon 301-721, Korea.
Hye Sook
HS
Jung
Dong Wook
DW
Kim
Young Suk
YS
Jo
Hyo Kyun
HK
Chung
Jung Hun
JH
Song
Jong Sun
JS
Park
Ki Cheol
KC
Park
Su Hyeon
SH
Park
Jung Hwan
JH
Hwang
Ki-Won
KW
Jo
Minho
M
Shong
D000818:Animals; D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000032:analysis / Q000378:metabolism*; D013961:Thyroid Gland / Q000201:enzymology; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014443:Tyrosine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051057:Proto-Oncogene Proteins c-akt