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[MAP kinase module: role in the control of cell proliferation]
A Brunet1, J M Brondello, G L'Allemain
1Centre de Biochimie, CNRS, UMR 134, Université de Nice, France.
Comptes Rendus Des Seances De La Societe De Biologie Et De Ses Filiales
|January 1, 1995
Summary
The mitogen-activated protein kinase (MAPK) cascade is essential for cell cycle entry. Its activation, translocation to the nucleus, and specific phosphatases like MKP-1 regulate this process, with sustained MAPK activation being crucial for cell proliferation.
Area of Science:
- Cellular signaling pathways
- Signal transduction cascades
- Molecular biology
Context:
- The Raf/MAP kinase kinase kinase (MAPKKK)-->MAP kinase kinase (MAPKK)-->MAP kinase (MAPK)-->ribosomal S6 kinase (p90 RSK) cascade is vital for transmitting signals from cell surface receptors to the nucleus.
- This cascade is activated by both tyrosine kinase and G protein-coupled receptors, with all mitogens converging on the activation of p42 and p44 MAPK isoforms.
Purpose:
- To clone, epitope tag, and express hamster MAPKK and p44 MAPK in fibroblasts.
- To analyze the kinetics of MAPK activation, its subcellular localization, regulatory phosphorylation sites, and its role in initiating the cell cycle.
Summary:
- MAPK activation is rapid, biphasic, and persistent, with sustained activation correlating to cell cycle entry and requiring potent mitogens.
- MAPKK activation is rapid and persistent but does not differentiate between mitogenic and non-mitogenic factors, suggesting MAPK-level regulation by phosphatases like MKP-1.
- MAPK translocates to the nucleus, while upstream activators remain cytoplasmic, indicating MAPK's role as a cytoplasmic-to-nuclear signaling relay.
Impact:
- Interfering with the MAPK cascade (via antisense, dominant-negative mutants, or MKP-1) inhibits growth factor-induced G0 to G1 transition.
- Constitutively active MAPKK promotes autonomous cell growth and tumor formation, highlighting MAPK activation's necessity and sufficiency for cell cycle initiation.