Two ras pathways in fission yeast are differentially regulated by two ras guanine nucleotide exchange factors

Mol Cell Biol. 2002 Jul;22(13):4598-606. doi: 10.1128/mcb.22.13.4598-4606.2002.

Abstract

How a given Ras prreotein coordinates multiple signaling inputs and outputs is a fundamental issue of signaling specificity. Schizosaccharomyces pombe contains one Ras, Ras1, that has two distinct outputs. Ras1 activates Scd1, a presumptive guanine nucleotide exchange factor (GEF) for Cdc42, to control morphogenesis and chromosome segregation, and Byr2, a component of a mitogen-activated protein kinase cascade, to control mating. So far there is only one established Ras1 GEF, Ste6. Paradoxically, ste6 null (ste6 Delta) mutants are sterile but normal in cell morphology. This suggests that Ste6 specifically activates the Ras1-Byr2 pathway and that there is another GEF capable of activating the Scd1 pathway. We thereby characterized a potential GEF, Efc25. Genetic data place Efc25 upstream of the Ras1-Scd1, but not the Ras1-Byr2, pathway. Like ras1 Delta and scd1 Delta, efc25 Delta is synthetically lethal with a deletion in tea1, a critical element for cell polarity control. Using truncated proteins, we showed that the C-terminal GEF domain of Efc25 is essential for function and regulated by the N terminus. We conclude that Efc25 acts as a Ras1 GEF specific for the Scd1 pathway. While ste6 expression is induced during mating, efc25 expression is constitutive. Moreover, Efc25 overexpression renders cells hyperelongated and sterile; the latter can be rescued by activated Ras1. This suggests that Efc25 can recruit Ras1 to selectively activate Scd1 at the expense of Byr2. Reciprocally, Ste6 overexpression can block Scd1 activation. We propose that external signals can partly segregate two Ras1 pathways by modulating GEF expression and that GEFs can influence how Ras is coupled to specific effectors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Cell Cycle Proteins / metabolism*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Gene Deletion
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • MAP Kinase Kinase Kinases*
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism*
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / metabolism*
  • Schizosaccharomyces pombe Proteins*
  • Signal Transduction
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • ATP-Binding Cassette Transporters
  • Cell Cycle Proteins
  • Efc25 protein, S pombe
  • Fungal Proteins
  • Guanine Nucleotide Exchange Factors
  • Proto-Oncogene Proteins
  • STE6 protein, S pombe
  • Schizosaccharomyces pombe Proteins
  • scd1 protein, S pombe
  • Mitogen-Activated Protein Kinases
  • BYR2 protein, S pombe
  • MAP Kinase Kinase Kinases
  • Ras1 protein, S pombe
  • ras Proteins