A novel functional link between MAP kinase cascades and the Ras/cAMP pathway that regulates survival

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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Vera A Cherkasova1, Ryan McCully, Yunmei Wang

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Current Biology : CB
|July 18, 2003
PubMed

Insights

In yeast, mating MAP kinases Fus3 and Kss1 regulate survival by controlling the Ras/cAMP pathway. Loss of Fus3 elevates cAMP, impairing survival and stress resistance, highlighting MAPK control over Ras signaling.

Area of Science:

  • Cellular signaling pathways
  • Yeast genetics and molecular biology

Background:

  • Ras signaling controls proliferation and survival in yeast.
  • Mitogen-activated protein kinase (MAPK) cascades, including Fus3 and Kss1, are involved in growth and mating.
  • Cross-regulation between MAPK pathways and the Ras/cAMP pathway is suspected but lacks direct evidence.

Purpose of the Study:

  • To investigate the direct role of Fus3 and Kss1 MAP kinases in regulating the Ras/cAMP pathway.
  • To elucidate the mechanism by which MAPKs control Ras signaling and cellular survival.

Main Methods:

  • Genetic analysis of yeast mutants (S. cerevisiae).
  • Measurement of cyclic AMP (cAMP) levels.
  • Analysis of protein interactions and phosphorylation.
  • Assessment of cell survival and stress resistance.

Main Results:

  • Loss of Fus3 kinase activity leads to increased cAMP levels and reduced long-term survival and stress resistance.
  • These effects are dependent on Kss1 and Ras2, indicating pathway integration.
  • Activation of Kss1 increases cAMP, while mating receptor activation has minimal impact.
  • Fus3 and Kss1 physically associate with and phosphorylate Cdc25, a Ras guanine nucleotide exchange factor (GEF).

Conclusions:

  • Fus3 and Kss1 MAP kinases act upstream of the Ras/cAMP pathway to regulate survival in yeast.
  • MAPK-mediated phosphorylation of Cdc25 is a key mechanism for controlling Ras signaling networks.
  • This cross-regulation provides a link between mating pathways and cell survival/proliferation.

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