TY - JOUR
T1 - Dual function of Pin1 in NR4A nuclear receptor activation
T2 - Enhanced activity of NR4As and increased Nur77 protein stability
AU - van Tiel, Claudia M.
AU - Kurakula, Kondababu
AU - Koenis, Duco S.
AU - van der Wal, Erik
AU - de Vries, Carlie J.M.
N1 - Funding Information: This research forms part of the Project P1.02 NEXTREAM of the research program of the BioMedical Materials institute , co-funded by the Dutch Ministry of Economic Affairs . The financial contribution of the Netherlands Heart Foundation is gratefully acknowledged.
PY - 2012/10
Y1 - 2012/10
N2 - Nur77, Nurr1 and NOR-1 form the NR4A subfamily of the nuclear receptor superfamily and have been shown to regulate various biological processes among which are cell survival and differentiation, apoptosis, inflammation and metabolism. These nuclear receptors have been proposed to act in a ligand-independent manner and we aim to gain insight in the regulation of NR4A activity. A yeast two-hybrid screen identified the peptidyl-prolyl isomerase Pin1 as a novel binding partner of NR4As, which was confirmed by co-immunoprecipitation. Pin1 enhances the transcriptional activity of all three NR4A nuclear receptors and increases protein stability of Nur77 through inhibition of its ubiquitination. Enhanced transcriptional activity of NR4As requires the WW-domain of Pin1 that interacts with the N-terminal transactivation domain and the DNA-binding domain of Nur77. Most remarkably, this enhanced activity is independent of Pin1 isomerase activity. A systematic mutation analysis of all 17 Ser/Thr-Pro-motifs in Nur77 revealed that Pin1 enhances protein stability of Nur77 in an isomerase-dependent manner by acting on phosphorylated Nur77 involving protein kinase CK2-mediated phosphorylation of the Ser152-Pro153 motif in Nur77. Given the role of Nur77 in vascular disease and metabolism, this novel regulation mechanism provides perspectives to manipulate Nur77 activity to attenuate these processes.
AB - Nur77, Nurr1 and NOR-1 form the NR4A subfamily of the nuclear receptor superfamily and have been shown to regulate various biological processes among which are cell survival and differentiation, apoptosis, inflammation and metabolism. These nuclear receptors have been proposed to act in a ligand-independent manner and we aim to gain insight in the regulation of NR4A activity. A yeast two-hybrid screen identified the peptidyl-prolyl isomerase Pin1 as a novel binding partner of NR4As, which was confirmed by co-immunoprecipitation. Pin1 enhances the transcriptional activity of all three NR4A nuclear receptors and increases protein stability of Nur77 through inhibition of its ubiquitination. Enhanced transcriptional activity of NR4As requires the WW-domain of Pin1 that interacts with the N-terminal transactivation domain and the DNA-binding domain of Nur77. Most remarkably, this enhanced activity is independent of Pin1 isomerase activity. A systematic mutation analysis of all 17 Ser/Thr-Pro-motifs in Nur77 revealed that Pin1 enhances protein stability of Nur77 in an isomerase-dependent manner by acting on phosphorylated Nur77 involving protein kinase CK2-mediated phosphorylation of the Ser152-Pro153 motif in Nur77. Given the role of Nur77 in vascular disease and metabolism, this novel regulation mechanism provides perspectives to manipulate Nur77 activity to attenuate these processes.
KW - NR4A nuclear receptors
KW - Protein stability
KW - Protein-protein interaction
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=84864544409&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbamcr.2012.06.030
DO - https://doi.org/10.1016/j.bbamcr.2012.06.030
M3 - Article
C2 - 22789442
SN - 0167-4889
VL - 1823
SP - 1894
EP - 1904
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 10
ER -