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Rsk1 mediates a MEK-MAP kinase cell survival signal.
A Shimamura1, B A Ballif, S A Richards
1Department of Cell Biology, Department of Pediatric Hematology and Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston 02115, USA.
Current Biology : CB
|February 19, 2000
Summary
The serine/threonine kinase Rsk1, a downstream target of the MEK-MAP kinase pathway, promotes cell survival. Rsk1 directly phosphorylates the pro-apoptotic protein Bad, inhibiting its function and preventing cell death.
Area of Science:
- Cellular signaling
- Molecular biology
- Cancer research
Background:
- Growth factors activate cell survival pathways, including the MEK-MAP kinase cascade.
- The downstream components of the MEK-MAP kinase survival pathway in mammals were previously unknown.
Purpose of the Study:
- To identify downstream effectors of the MEK-MAP kinase cell survival pathway.
- To elucidate the role of Rsk1 in mediating cell survival signals.
Main Methods:
- Pharmacological inhibition of MEK (MAP kinase kinase).
- Utilized kinase-dead and constitutively active Rsk1 mutants.
- In vitro and in vivo phosphorylation assays.
- Site-directed mutagenesis of the pro-apoptotic protein Bad.
Main Results:
- Rsk1, a downstream target of MEK-MAP kinase, plays a pro-survival role.
- Rsk1 directly phosphorylates the pro-apoptotic protein Bad at specific serine residues.
- Phosphorylation of Bad by Rsk1 abrogates its pro-apoptotic function, conferring cell survival.
- Constitutively active Rsk1 promotes Bad phosphorylation and cell survival, while kinase-inactive mutants antagonize this effect.
Conclusions:
- Rsk1 acts as a crucial transducer of the MEK-MAP kinase survival signal.
- Rsk1 mediates cell survival, in part, through the direct phosphorylation of Bad.