Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta.
The phosphatase and tensin homologue (PTEN) tumor suppressor is a phosphatidylinositol D3-phosphatase that counteracts the effects of phosphatidylinositol 3-kinase and negatively regulates cell growth and survival. PTEN is itself regulated by phosphorylation on multiple serine and threonine residues in its C terminus. Previous work has implicated casein kinase 2 (CK2) as the kinase responsible for this phosphorylation. Here we showed that CK2 does not phosphorylate all sites in PTEN and that glycogen synthase kinase 3beta (GSK3beta) also participates in PTEN phosphorylation. Although CK2 mainly phosphorylated PTEN at Ser-370 and Ser-385, GSK3beta phosphorylated Ser-362 and Thr-366. More importantly, prior phosphorylation of PTEN at Ser-370 by CK2 strongly increased its phosphorylation at Thr-366 by GSK3beta, suggesting that the two may synergize. Using RNA interference, we showed that GSK3 phosphorylates PTEN in intact cells. Finally, PTEN phosphorylation was affected by insulin-like growth factor in intact cells. We concluded that multiple kinases, including CK2 and GSK3beta, participate in PTEN phosphorylation and that GSK3beta may provide feedback regulation of PTEN.
Al-Khouri
Anna Maria
AM
Inflammatory and Infectious Disease Center, The Burnham Institute, La Jolla, California 92037, USA.
Ma
Yuliang
Y
Togo
Summanuna H
SH
Williams
Scott
S
Mustelin
Tomas
T
D000595:Amino Acid Sequence; D047390:Casein Kinase II / Q000378:metabolism*; D002460:Cell Line; D005982:Glutathione Transferase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010449:Peptide Mapping; D010455:Peptides / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011328:Prions / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology
D007328:Insulin; D010455:Peptides; D011328:Prions; D013912:Threonine; D012694:Serine; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D047390:Casein Kinase II; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D014357:Trypsin