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CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases
M Sheng1, M A Thompson, M E Greenberg
1Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Science (New York, N.Y.)
|June 7, 1991
Summary
Calcium ions (Ca2+) trigger gene induction via Ca(2+)-calmodulin-dependent protein kinases (CaM kinases) activating the CREB transcription factor. Phosphorylation of CREB at Ser133 by CaM kinases is crucial for this electrical signal transduction to the nucleus.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Signaling
Background:
- Membrane depolarization triggers cellular responses, including gene induction.
- Calcium ions (Ca2+) play a critical role in mediating these responses.
- The adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) is a known transcription factor involved in cellular signaling.
Purpose of the Study:
- To investigate the mechanism by which Ca2+ mediates gene induction following membrane depolarization.
- To determine the role of Ca(2+)-calmodulin-dependent protein kinases (CaM kinases) and CREB in this process.
Main Methods:
- Investigated Ca2+ signaling pathways.
- Examined the function of CREB as a Ca2+-regulated transcription factor.
- Assessed the phosphorylation of CREB by CaM kinases in vitro and in vivo.
- Utilized site-directed mutagenesis to alter CREB phosphorylation sites.
Main Results:
- CREB acts as a Ca2+-regulated transcription factor.
- Depolarization-activated CaM kinases I and II phosphorylate CREB.
- Serine 133 (Ser133) on CREB is the primary site of CaM kinase-mediated phosphorylation.
- Mutation of Ser133 significantly impairs CREB's response to Ca2+.
Conclusions:
- CaM kinases act as a conduit for electrical signals to the nucleus.
- CREB integrates both Ca2+ and cAMP signaling pathways.
- Ca2+ influx following membrane depolarization is a key regulator of gene expression via CREB phosphorylation.
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