Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.
Silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) is a transcriptional corepressor that participates in diverse signaling pathways and human diseases. However, regulation of SMRT stability remains largely unexplored. We show that the peptidyl-prolyl isomerase Pin1 interacts with SMRT both in vitro and in mammalian cells. This interaction requires the WW domain of Pin1 and SMRT phosphorylation. Pin1 regulates SMRT protein stability, thereby affecting SMRT-dependent transcriptional repression. SMRT phosphorylation at multiple sites is required for Pin1 interaction, and these sites can be phosphorylated by Cdk2, which interacts with SMRT. Cdk2-mediated phosphorylation of SMRT is required for Pin1 binding and decreases SMRT stability, whereas mutation of these phosphorylation sites abrogates Pin1 binding and stabilizes SMRT. Finally, decreases in SMRT stability occur in response to the activation of Her2/Neu/ErbB2, and this receptor functions upstream of both Pin1 and Cdk2 in the signaling cascade that regulates SMRT stability and cellular response to tamoxifen.
Department of Biochemistry, School of Medicine, Case Western Reserve University, Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Kristopher J
KJ
Stanya
Yu
Y
Liu
Anthony R
AR
Means
Hung-Ying
HY
Kao
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020890:Neuregulin-1 / Q000494:pharmacology; D056985:Nuclear Receptor Co-Repressor 2; D010446:Peptide Fragments / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000819:agonists / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D020032:Tyrphostins / Q000494:pharmacology
D052160:Benzothiazoles; D051357:Cyclin-Dependent Kinase 2; D016213:Cyclins; D004268:DNA-Binding Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D020890:Neuregulin-1; D056985:Nuclear Receptor Co-Repressor 2; D010446:Peptide Fragments; D019696:Peptidylprolyl Isomerase; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D013629:Tamoxifen; D020032:Tyrphostins; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; C098214:tyrphostin AG825; C016601:afimoxifene; C508053:ERBB2 protein, human; C495894:CDK2 protein, human; C000606846:PIN1 protein, human; C000606850:Pin1 protein, mouse