A mechanism for cell-cycle regulation of MAP kinase signaling in a yeast differentiation pathway.
Yeast cells arrest in the G1 phase of the cell cycle upon exposure to mating pheromones. As cells commit to a new cycle, G1 CDK activity (Cln/CDK) inhibits signaling through the mating MAPK cascade. Here we show that the target of this inhibition is Ste5, the MAPK cascade scaffold protein. Cln/CDK disrupts Ste5 membrane localization by phosphorylating a cluster of sites that flank a small, basic, membrane-binding motif in Ste5. Effective inhibition of Ste5 signaling requires multiple phosphorylation sites and a substantial accumulation of negative charge, which suggests that Ste5 acts as a sensor for high G1 CDK activity. Thus, Ste5 is an integration point for both external and internal signals. When Ste5 cannot be phosphorylated, pheromone triggers an aberrant arrest of cells outside G1 either in the presence or absence of the CDK-inhibitor protein Far1. These findings define a mechanism and physiological benefit of restricting antiproliferative signaling to G1.
Strickfaden
Shelly C
SC
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Winters
Matthew J
MJ
Ben-Ari
Giora
G
Lamson
Rachel E
RE
Tyers
Mike
M
Pryciak
Peter M
PM
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D055672:Static Electricity
D048868:Adaptor Proteins, Signal Transducing; C082721:CLN2 protein, S cerevisiae; D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; C081353:FAR1 protein, S cerevisiae; D012097:Repressor Proteins; C080321:STE5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases