Tip60 and HDAC7 interact with the endothelin receptor a and may be involved in downstream signaling.
Endothelins exert their biological effects through G protein-coupled receptors. However, the precise mechanism of downstream signaling and trafficking of the receptors is largely unknown. Here we report that the histone acetyltransferase Tip60 and the histone deacetylase HDAC7 interact with one of the ET receptors, ETA, as determined by yeast two-hybrid analysis, glutathione S-transferase pull-down assays, and co-immunoprecipitation from transfected COS-7 cells. In the absence of ET-1, Tip60 and HDAC7 were localized mainly in the cell nucleus while ETA was predominantly confined to the plasma membrane. Stimulation with ET-1 resulted in the internalization of ETA to the perinuclear compartment and simultaneously in the efflux of Tip60 and HDAC7 from the nucleus to the same perinuclear compartment where each protein co-localized with the receptor. Upon co-transfection with ETA into COS-7 cells, Tip60 strongly increased ET-1-induced ERK1/2 phosphorylation, whereas HDAC7 had no significant effect. We thus suggest that protein acetylase and deacetylase interact with ETA in a ligand-dependent fashion and may participate in ET signal transduction.
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
H J
HJ
Lee
M
M
Chun
K V
KV
Kandror
D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009130:Muscle, Smooth; D051381:Rats; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D014162:Transfection
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases