Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family.
The members of the TCL1 proto-oncogene family (TCL1, MTCP1, and TCL1b) bind to Akt1, increasing its phosphorylation status and kinase activity. This is thought to be secondary to the formation of TCL1-Akt oligomers within which Akt is preferentially phosphorylated. Here we show that, in contrast to Akt1 and Akt2, which bind to all members of the TCL1 family, Akt3 specifically interacts with TCL1 but not with MTCP1 or TCL1b. This association is functional, as the presence of TCL1 but not MTCP1 or TCL1b increased Akt3 kinase activity in in vitro kinase assays. Functional specificity is determined by the Akt pleckstrin homology domain as chimeric Akt1, where Akt1 PH domain was replaced by that of Akt3 was no longer able to interact with MTCP1 or TCL1b and its kinase activity was solely enhanced by TCL1. Moreover, we show that, in TCL1-overexpressing SUPT-11 T-cell leukemia and P3HR-1 Burkitt's lymphoma cell lines, TCL1 interacts with endogenous Akt1, Akt2, and Akt3. TCL1 enhanced hetero-oligomerization of Akt1 with Akt3 and as a consequence facilitated transphosphorylation of Akt molecules, which may contribute to Akt activation and TCL1-induced leukemogenesis in vivo.
Laine
Jarmo
J
Division of Immunology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Künstle
Gerald
G
Obata
Toshiyuki
T
Noguchi
Masayuki
M
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008322:Mammals; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015183:Restriction Mapping; D013601:T-Lymphocytes; D014162:Transfection
D017931:DNA Primers; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C090851:TCL1A protein, human; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt