Phosphotyrosine signaling: evolving a new cellular communication system

Abstract

Tyrosine phosphorylation controls many cellular functions. Yet the three-part toolkit that regulates phosphotyrosine signaling-tyrosine kinases, phosphotyrosine phosphatases, and Src Homology 2 (SH2) domains-is a relatively new innovation. Genomic analyses reveal how this revolutionary signaling system may have originated and why it rapidly became critical to metazoans.

Figure 1. The Writer, Reader, Eraser pTyr Toolkit

(A) In pTyr signaling, the tyrosine kinase (TyrK), Src Homology 2 (SH2), and phosphotyrosine phosphatase (PTP) domains form a highly interdependent signaling platform. This platform serves as the writer, reader, and eraser modules, respectively, for processing pTyr marks. (B) Components of pTyr signaling can be used to build complex circuits. For example, recruitment of an SH2-TyrK protein to an initiating pTyr site can lead to amplification of tyrosine phosphorylation through a positive feedback loop.

Figure 2. Evolution of pTyr signaling

Shown is a possible path for the emergence of phosphotyrosine (pTyr) signaling. . We postulate three successive stages, each represented by what is observed in a modern organism. The thickness of the tree reflects the approximate degree of usage of pTyr signaling (thicker lines means more usage). Stage 1 (exemplified by the budding yeast Saccharomyces cerevisiae) reflects the situation in early eukaryotes, in which PTPs emerged but were limited in number and complexity. They were most likely used to reverse or process sporadic cross-phosphorylation of tyrosine residues by Ser/Thr kinases. S. cerevisiae has <5 PTP proteins and no functional SH2 or TyrK domains. Stage 2 reflects systems in which functional SH2 domains emerged that were able to bind to pTyr motifs. Together with Ser/Thr kinases with increased cross-reactivity for Tyr (such as tyrosine kinase-like or dual specificity Ser/Thr kinases), these systems may reflect the most primitive of pTyr writer/reader/eraser systems. However, the lack of a dedicated Tyr kinase may have limited the utility and expansion of this toolkit. This stage is potentially represented by the slime mold, Dictyostelium discoideum. Stage 3 reflects systems that evolved after the emergence of the modern TyrK domain. We postulate that the full writer/reader/eraser system was of so much greater utility, that its use expanded dramatically. This likely resulted in many more proteins in these families, as well as much more complex, multi-domain architectures than those seen in the earlier stages. This stage is represented by both the multicellular metazoan and unicellular choanoflagellate lineages.