![]() ![]() Raf Activation and 14-3-3?Īlthough conceptually similar, there are distinct differences between all three signaling complexes. Despite these differences, the similarities between AKAP79 and Ste5p provide an oppportunity to speculate on other proteins involved in signaling that may also serve as a scaffold. Another distinction is that the AKAP79 complex is able to respond to three distinct activation signals, whereas a single upstream event, the activation of Ste20p, is sufficient to transduce a signal from one kinase to the next in the Ste5p signaling scaffold. AKAP79, on the other hand, restricts the location of PKA, PKC and calcineurin, enzymes with broad specificity. To insure efficient transduction of this signal, both intermediary kinases Ste11p and Ste7p have limited substrate specificity and bind to precise sites on the scaffold protein. While AKAP79 dictates the subcellular location of two multifunctional kinases and a broad specificity phosphatase, Ste5p orchestrates the location and activation of three interrelated kinases. However, there are important differences. Both Ste5p and AKAP79 provide an additional level of regulation for protein phosphorylation events by restricting the action of kinases and phosphatases through protein-protein interactions. The apparent coordination of synaptic signaling by a modular anchoring protein raises the intriguing possibility that AKAP79 displays a similar function to the Ste5p scaffold. Recent studies suggest that there may be additional components of the complex as the G protein β subunit, STE4 and possibly Ste20p interact with Ste5p ( These findings were confirmed through deletion analysis demonstrating that a Ste5p 1-336 fragment binds Fus3p or Kss1p whereas the Ste5p 336-917 fragment only binds Ste7p and Ste11p. Initial clues to its function came from yeast two-hybrid experiments reported by three groups which demonstrated that Ste11p and Ste7p bind to distinct sites on Ste5p while Fus3p and Kss1p compete for another site on the protein ( Figure 2). Sterile 5 was initially identified as a recessive mutation in the yeast mating pathway twenty years ago and has recently been shown to encode a 917 amino acid protein. This signaling pathway is tightly controlled because each enzyme associates with a scaffold protein called Ste5p ( Figure 2). This leads to the stimulation of Ste11p, a MEKK homolog, which phosphorylates and activates Ste7p, a MEK homolog, which in turn, phosphorylates and activates the MAPK homologs, Fus3p or Kss1p. The pheromone mating response is initiated through ligand induced changes in G-protein linked receptors to activate a kinase, Ste20p. The kinases in these pathways may be segregated through association with scaffold proteins. ![]()
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