Related Experiment Videos
Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase
J Xing1, D D Ginty, M E Greenberg
1Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression.
Insights
Growth factors activate gene expression through a pathway involving RAS and mitogen-activated protein kinase (MAPK). This pathway activates RSK2, which phosphorylates cyclic adenosine monophosphate response element-binding protein (CREB), a key transcription factor.
Area of Science:
- Molecular Biology
- Cell Signaling
- Gene Regulation
Background:
- Growth factors regulate gene transcription via signaling pathways.
- Cyclic adenosine monophosphate response element-binding protein (CREB) is a key transcription factor activated by growth factors.
- The RAS-mitogen-activated protein kinase (MAPK) pathway mediates growth factor signaling.
Purpose of the Study:
- To elucidate the signaling pathway linking growth factors to CREB activation.
- To identify the specific kinase responsible for CREB phosphorylation at serine-133.
- To define the role of RSK2 in growth factor-induced gene expression.
Main Methods:
- Purification, sequencing, and biochemical characterization of CREB kinase.
- In vitro and in vivo assays to assess RSK2 activity in CREB phosphorylation.
- Analysis of growth factor-induced gene expression.
Main Results:
- CREB kinase was identified as RSK2, a member of the pp90(RSK) family.
- RSK2 mediates growth factor-induced phosphorylation of CREB at serine-133.
- RSK2 plays a critical role in transmitting growth factor signals to the nucleus for gene activation.
Conclusions:
- RSK2 is a key mediator in the RAS-MAPK pathway, linking growth factor stimulation to CREB activation.
- This study defines a novel cellular function for RSK2 in regulating gene expression.
- The findings provide a detailed mechanism for how growth factor signals are transmitted to activate transcription.