Signal Transduction via the Multi-Step Phosphorelay: Not Necessarily a Road Less Traveled

It is worth noting that the reported phosphorelays, as well as the putative phosphorelay candidates mentioned above, govern major developmental commitments, decisions that should not be lightly made. For instance, activation of the Kin-Spo0 pathway of B. subtilis or the AsgA pathway of M. xanthus ultimately results in sporulation. BvgS, as well as several other BvgS family members, is involved in regulation of a wide variety of virulence factors. Likewise, the RcaE-RcaC chromatic adaptation system modulates dramatic changes in the ratio of the two major chromoproteins of the light harvesting system, which accounts for up to 50% of the total cellular protein. Inappropriate activation of any of these pathways would undoubtedly have deleterious effects on the cell, at the very least a grave misuse of cellular resources.The realization that phosphorelays may be more common than previously appreciated, coupled with the identification of multiple architectural configurations, suggests that these circuits have special signaling properties. In contrast to, for example, a MAP kinase phosphorylation cascade, where activation of downstream kinases by phosphorylation increases the flow of phosphoryl groups through the pathway, the relay approach offers no signal amplification beyond the initial autophosphorylation of H1. Perhaps instead the relay establishes a threshold that requires a signal of minimum proportion or duration to be overcome before a response is seen. The most important advantage of the multi-step relay, however, may be that it provides the potential for multiple regulatory checkpoints (5xGrossman, A.D. Annu. Rev. Genet. 1995; 29: 477–508Crossref | PubMedSee all References, 6xSee all References). In systems with unlinked components, transcriptional regulation of relay components provides one mechanism of control, as has been demonstrated in the Kin-Spo0 pathway. In cases such as BvgS or Sln1p, the presence of several relay steps in one protein may increase signaling efficiency and reduce non-specific crosstalk from other pathways. Phosphatases that act on specific relay sites provide another versatile mechanism for regulating signal flow in phosphorelays. Finally, the multiple phosphorylation sites of the phosphorelay could provide junction points for communicating with other signaling pathways, perhaps endowing the cell with sophisticated information-processing capabilities far beyond the simplistic linear sequence of events depicted in Figure 3Figure 3.The elegant characterization of the yeast Sln1 pathway by Posas et al. 1996xPosas, F, Wurgler-Murphy, S.M, Maeda, T, Witten, E.A, Thai, T.C, and Saito, H. Cell. 1996; 86Abstract | Full Text | Full Text PDF | PubMed | Scopus (616)See all ReferencesPosas et al. 1996 is doubly noteworthy. It provides the first demonstration that proteins of the eukaryotic two-component family undergo phosphorylation reactions characteristic of their bacterial counterparts, and at the same time broadens our view of signal transduction mechanisms in bacteria to emphasize the importance of the multi-step phosphorelay as a versatile and sophisticated signaling strategy exploited by prokaryotes and eukaryotes alike.