The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2.
The corepressors N-CoR and SMRT partner with histone deacetylases (HDACs) in diverse repression pathways. We report here that GPS2, a protein involved in intracellular signaling, is an integral subunit of the N-CoR-HDAC3 complex. We have determined structural motifs that direct the formation of a highly stable and active deacetylase complex. GPS2 and TBL1, another component of the N-CoR-HDAC3 complex, interact cooperatively with repression domain 1 of N-CoR to form a heterotrimeric structure and are indirectly linked to HDAC3 via an extended N-CoR SANT domain that also activates latent HDAC3 activity. More importantly, we show here that the N-CoR-HDAC3 complex inhibits JNK activation through the associated GPS2 subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP-1 function.
Zhang
Jinsong
J
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Kalkum
Markus
M
Chait
Brian T
BT
Roeder
Robert G
RG
D000595:Amino Acid Sequence; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology*; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000302:isolation & purification / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000302:isolation & purification / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D046911:Macromolecular Substances; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C103316:GPS2 protein, human; C539127:NCOR1 protein, human