Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor.
Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232. Mutations in these kinases have opposite effects on receptor transcriptional activity in vivo. Receptor-dependent transcriptional enhancement is reduced in yeast strains deficient in the catalytic (p34CDC28) or certain regulatory (cyclin) subunits of CDK complexes and is increased in a strain devoid of the mammalian MAPK homologs FUS3 and KSS1. These findings indicate that the glucocorticoid receptor is a target for multiple kinases in vivo, which either positively or negatively regulate receptor transcriptional enhancement. The control of receptor transcriptional activity via phosphorylation provides an increased array of regulatory inputs that, in addition to steroid hormones, can influence receptor function.
Krstic
M D
MD
Biochemistry and Biophysics, University of California, San Francisco, 94143-0445, USA.
Rogatsky
I
I
Yamamoto
K R
KR
Garabedian
M J
MJ
D000818:Animals; D042846:CDC2-CDC28 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D016213:Cyclins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000032:analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014158:Transcription, Genetic
D016213:Cyclins; D010748:Phosphopeptides; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases