Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae

Abstract

Signaling pathways that activate different mitogen-activated protein kinases (MAPKs) elicit many of the responses that are evoked in cells by changes in certain environmental conditions and upon exposure to a variety of hormonal and other stimuli. These pathways were first elucidated in the unicellular eukaryote Saccharomyces cerevisiae (budding yeast). Studies of MAPK pathways in this organism continue to be especially informative in revealing the molecular mechanisms by which MAPK cascades operate, propagate signals, modulate cellular processes, and are controlled by regulatory factors both internal to and external to the pathways. Here we highlight recent advances and new insights about MAPK-based signaling that have been made through studies in yeast, which provide lessons directly applicable to, and that enhance our understanding of, MAPK-mediated signaling in mammalian cells.

Figure 1. Schematic diagrams of the MAPK signaling pathways in S. cerevisiae

Symbols are: protein kinases, ovals; GTP-binding proteins, diamonds; scaffold, adaptor, and activating proteins, rectangles; cell surface proteins, trapezoids; activation, arrows; inhibition, T-bars; direct action, smooth lines; indirect action (or unknown molecular mechanism), squiggly lines. For clarity, not all factors and interactions are shown, connections to other pathways and processes upstream of the MAPKs are omitted, and direct targets of the MAPKs are not included (see the text for these details).

Figure 2. Mechanisms of MAPK regulation of yeast cell cycle progression

Fus3 (in response to pheromone) and Hog1 (in response to hyperosmotic stress) impose cell cycle arrest in the G1 phase via their direct phosphorylation of two different proteins (Far1 and Sic1, respectively) that act as direct inhibitors of yeast CDK1 (Cdc28). Hog1 also imposes cell cycle arrest in the G2 phase via blocking the action of a protein kinase (Hsl1) necessary for initiating the ubiquitin- and proteasome-mediated destruction of a protein kinase, Swe1 (mammalian ortholog, Wee1), that is a specific antagonist of cyclin B (Clb)-bound CDK1. Slt2/Mpk1 (in response to cell wall stress) imposes G2 cell cycle arrest via inhibition (direct or indirect) of the phosphoprotein phosphatase, Mih1 (mammalian ortholog, Cdc25C), that is necessary to reverse the inhibitory tyrosine-specific phosphorylation installed on CDK1 by Swe1. See the text for further details.

Figure 3. Mechanisms of MAPK regulation of transcriptional initiation in yeast

Inactive Kss1 resides mainly in the nucleus and acts as a transcriptional co-repressor by forming quaternary complexes with the heterodimeric transcription factor, Tec1-Ste12, and the repressors, Dig1 and Dig2. Ste7-dependent dual phosphorylation activates Kss1, permitting it to phosphorylate the Dig proteins and Ste12, thereby leading both to derepression and to activation of the transcription factor. Inactive Hog1 resides mainly in the cytosol and Pbs2-dependent dual phosphorylation activates Hog1 and promotes its translocation into the nucleus, where it stimulates transcription at some promoters, in part, by binding to and converting a transcriptional repressor, the Sko1-Cyc8/Ssn6-Tup1 complex, into a transcriptional activator, and, in part, by affecting the state of local chromatin modification via recruitment of a specific histone deacetylase, the Sin3-Rpd3 complex. Active Hog1 can also stimulate transcription at other promoters by phosphorylating and binding to a transcriptional activator, such as Hot1, and thereby serving as an adaptor or mediator that also binds to and recruits RNA polymerase II holoenzyme. See the text for additonal details.

Figure 4. Mechanism of MAPK-directed developmental commitment and cell fate determination in yeast

Fus3 (in response to pheromone) specifically phosphorylates and promotes the ubiquitin-dependent and proteasome-mediated destruction of the transcription factor, Tec1, which is uniquely required for induction of the genes necessary for filamentous growth (see Fig. 3). The same site in Tec1 is not a substrate for Kss1. In this way, even though Kss1 is also activated (albeit transiently) in response to pheromone, a filamentation response is precluded. Hence, this process provides an elegantly simple mechanism to ensure that, once a haploid cell is exposed to pheromone, it is irrevocably committed to the mating response. Similar mechanisms are likely involved in directing the development transitions and in dictating the cell fate commitments observed in mammalian cell differentiation.