Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV.
Activity-regulated transcription has been implicated in adaptive plasticity in the CNS. In many instances, this plasticity depends upon the transcription factor CREB. Precisely how neuronal activity regulates CREB remains unclear. To address this issue, we examined the phosphorylation state of components of the CREB transcriptional pathway. We show that NMDA activates transcription of CREB-responsive genes in hippocampal neurons, with ERK responsible for persistent CREB phosphorylation and CaM kinase IV (CaMKIV) responsible for phosphorylating the CREB coactivator, CBP. Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301.
Impey
Soren
S
The Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, L-474, Portland, OR 97201, USA. impeys@ohsu.edu
Fong
Amy L
AL
Wang
Yanhong
Y
Cardinaux
Jean Rene
JR
Fass
Daniel M
DM
Obrietan
Karl
K
Wayman
Gary A
GA
Storm
Daniel R
DR
Soderling
Thomas R
TR
Goodman
Richard H
RH
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D019556:COS Cells; D050882:CREB-Binding Protein; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D016202:N-Methylaspartate; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517686:Camk4 protein, rat; D020928:Mitogen-Activated Protein Kinases