The Molecular History of Eukaryotic Life MAP Kinase Cascades
MAPK external stimulus effect Fus3p pheromone response mating Kss1p starvation filamentation Hog1p high osmolarity osmolyte synthesis Mpk1p Hypotonic shock cell wall remodeling Mlp1p unknown possibly similar to Mpk1p Smk1p carbon and nitrogen deprivation sporulation
David Nelson Dec. 13, 2000 The MAP (mitogen activated protein) kinase cascade is a useful example to follow back in time. The MAP kinases exist in yeast, and since the whole genome is known, all the MAP kinases can be identified in yeast. There are six of these genes. (Trends in Genetics 14, 151-155 1998 and Cell 80, 187-197 1995). They are FUS3, KSS1, HOG1, MPK1, SMK1 and MLP1. A table showing the actions of these MAPKs is given below.All of these kinases are important for some aspect of the yeast life cycle and its response to its evironment. However, all six of these genes can be deleted in a single host strain and the cells will live, though they wont be very robust (Cell 91, 673-674 1997). They will not be able to respond to external signals and they have to be treated pretty gently. Two of these MAPKs share parts of their signal transduction pathways. This poses the difficult question of how the final end response is unique when the middle of the pathway is the same. Fus3p in the mating pheromone pathway and kss1 in the filamentation pathway share three kinases in common. These are STE20, STE11 and STE7. These are the yeast equivalents of human PAK, MEKK and MEK. [Note: yeast mutants that are defective in mating are called STErile mutants and their genes are numbered as STE#. There are dozens of sterile mutants in yeast]. The solution to this problem is found in inhibitory functions for both Fus3p and Kss1p. These inhibitory functions are independent of their kinase activities. If Fus3p is deleted rather than inactivated by a point mutation, the yeast cells can still mate. It has been suggested that Kss1p substitutes for Fus3p in this case. Surprisingly, the filamentation pathway is also activated under these conditions (addition of pheromone). The interpretation of these results is that Fus3p is inhibitory to the activation of filamentation and it normally blocks this pathway. If a point mutation is used in Fus3p, then the inhibitory role of Fus3p is preserved and the filamentation pathway is not activated by pheromone. There is one problem with this model. If Fus3p inhibits filamentation, then how can filamentation ever occur? Somehow this inhibition must be overcome when a filamentation signal is detected. One way this might happen is by forming complexes of the shared components with their unique MAPKs. In effect, this would make a unique complex. A protein called Ste5p has been shown to form a complex with Ste11p, Ste7p and Fus3p. The complex may make the whole pathways behavior unique even though there are shared components. The exact details of this complex regulation have not been worked out. The sensor of the external conditions for these pathways is not known in all cases. The pheromone pathway for mating has two seven transmembrane receptors STE2 for the alpha mating factor and STE3 for the a mating factor. These have a heterotrimeric G protein. The HOG1 pathway has two independent osmosensors. Neither of these is a seven transmembrane receptor. One called SHO1 has an SH3 domain in the cytoplasm that binds to a MAPKK called PBS2. This phosphorylates and activates HOG1. The other osmosensor is a histidine kinase that also feeds into the PBS2 kinase. The histidine kinase and its target Ssk1p are similar to a two component regulatory signaling system seen in bacteria. Return to index References