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Phosphotyrosine Signaling: Evolving a New Cellular Communication System

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Phosphotyrosine Signaling: Evolving a New Cellular Communication System View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Leading Edge Essay Phosphotyrosine Signaling: Evolving a New Cellular Communication System Wendell A. Lim1,2,* and Tony Pawson3,4,* 1Howard Hughes Medical Institute 2Department of Cellular and Molecular Pharmacology University of California, San Francisco, San Francisco, CA 94158, USA 3Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada 4Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada *Correspondence: [email protected] (W.A.L.), [email protected] (T.P.) DOI 10.1016/j.cell.2010.08.023 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. Throughout human history, new technolo- (TyrK) phosphorylate specific target with an evolutionary process? Proteins gies and technological platforms have tyrosine residues, phosphotyrosine phos- that bind or remove a posttranslational constantly been invented. Only a small phatases (PTP) remove the phosphates, modification would seem useless without fraction of these technologies go on to and Src Homology 2 (SH2) domains an enzyme to generate the modification be widely adopted, but these can recognize the modifications (Pawson and, in principle, would not provide ultimately have transformational conse- 1995). Together, these three modules a fitness advantage leading to its retention quences. In the evolutionary history of form the ‘‘writer,’’ ‘‘eraser,’’ and ‘‘reader’’ and spread. The pTyr signaling platform living organisms, we know that innovative toolkit that is common to many diverse provides a case study to look for plausible molecular systems have appeared at key cellular information processing platforms stepwise pathways of the evolution of points in time, and these are thought to (Figure 1A). A rich array of diverse and a multipart system. have played a transformative role in major complex regulatory schemes can be Here, we reconstruct a possible history evolutionary transitions in the tree of life. achieved through the dynamic interplay for the evolution of pTyr signaling. This But how do such innovative molecular of these three modular functions (Pawson reconstruction is based on the recent systems emerge, and how and why do et al., 1993; Pawson, 1995; Bhattachar- sequencing of the genomes of a number some proliferate and become stably yya et al., 2006; Kholodenko, 2006). of organisms that originated both before adopted by subsequent lineages? A combination of these modules can and after the emergence of metazoans An example of such an innovative lead to higher-order functions (Figure 1B). from single-celled eukaryotic ancestors molecular system is phosphotyrosine For example, there are several proteins (King et al., 2008). The genome sequence (pTyr)-based signal transduction. This containing a combination of SH2 and of the choanoflagellate, Monosiga brevi- molecular system for transmitting cellular kinase domains that can generate collis, has been particularly illuminating regulatory information is estimated to positive feedback (phosphorylation of as choanoflagellates are thought to be have appeared relatively recently in the tyrosine sites leads to SH2-mediated one of the closest single-celled relatives history of life—600 million years ago, recruitment of the kinase, and subse- of metazoans. We present a model for just prior to the emergence of multicellular quently, more extensive phosphorylation) how this three-part signaling system animals (King et al., 2003; Pincus et al., (Pawson, 2004). Similarly SH2-phospha- could have plausibly evolved in a stepwise 2008; Manning et al., 2008). The pTyr sig- tase domain combinations can generate manner. We propose that once the naling system has become an essential negative feedback (Tonks and Neel, complete three-part system was in place, part of metazoan biology. For example, 2001). it may have rapidly taken hold in subse- pTyr signaling plays a central role in many The three-part pTyr signaling toolkit quent lineages because it could generate cell-to-cell communication pathways, thus raises a classic question in evolu- new regulatory behaviors without signifi- including those that regulate proliferation, tionary biology: how do complex, interde- cant cross-interference with existing differentiation, adhesion, hormone res- pendent systems arise? It is clear why regulatory circuits. We also discuss the ponses, and immune defense (Hunter, a new system encompassing a writer, possible role of this new communication 2009). eraser, and reader might be extremely system in facilitating the transformative In modern metazoans, pTyr signaling is useful. But, given their interdependence, evolutionary shift to multicellularity. mediated by a toolkit of three distinct how could these individual components Given the incomplete record, however, functional modules: tyrosine kinases arise in a stepwise fashion consistent such an evolutionary reconstruction is Cell 142, September 3, 2010 ª2010 Elsevier Inc. 661 by an upstream Ser/Thr kinase on both a Thr and Tyr residue within its activation loop; Cdk1 is phosphorylated on Tyr14 by the inhibitory kinase Wee1). These tyrosine modifications are clearly not recognized by SH2 domains, but they exert direct allosteric effects within the proteins in which they occur. Thus, PTP domains may have provided a fitness benefit by negatively modulating these rare but functionally important phosphor- ylation events. Consistent with this model, the proteins PTP2 and PTP3 in yeast clearly have a functionally important role in downregulating MAPK-mediated sig- naling in response to pheromones or osmolarity changes, explaining their Figure 1. The Writer, Reader, Eraser pTyr Toolkit fitness benefit (Pincus et al., 2008). In (A) In pTyr signaling, the tyrosine kinase (TyrK), Src Homology 2 (SH2), and phosphotyrosine phosphatase addition, PTPs may have played a general (PTP) domains form a highly interdependent signaling platform. This platform serves as the writer, reader, role buffering against the occasional 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 harmful stray phosphorylation of function- SH2-TyrK protein to an initiating pTyr site can lead to amplification of tyrosine phosphorylation through ally important tyrosines. a positive feedback loop. Where did these PTPs come from? PTPs are likely to have arisen from highly speculative. For example, we have tyrosine phosphatase activity. We a common ancestor of the related dual- cannot rule out more complex paths refer to the single putative ‘‘SH2’’ domain specificity phosphatases, which are also involving cycles of evolutionary gain and in yeast, found within the gene Spt6,as found in most single-celled eukaryotes loss of components, nor the possibility a proto-SH2 domain because it does not (Kennelly, 2001; Alonso et al., 2004). that similar components in distinct line- show pTyr binding (the domain has been Dual-specificity phosphatases are cata- ages have independent origins. Nonethe- reported to show phospho-Ser/Thr lytic domains that can dephosphorylate less, this model may provide a useful binding; Dengl et al., 2009). Thus, func- both pSer/Thr and pTyr substrates. The framework for focusing studies of pTyr tionally, it cannot be considered a PTP and dual-specificity phosphatase signaling origins and the origins of analo- ‘‘reader’’ domain that is part of a pTyr catalytic domains are distinct but are gous multicomponent signaling plat- regulatory system. These observations evolutionarily related. They share a forms. suggest a simple model: the first step in common fold and the core catalytic motif We describe three possible stages in the evolution of the three-part pTyr HC(X)5R, in which a phosphocysteine the emergence of the modern pTyr signaling machinery was likely to have enzyme intermediate is generated during signaling toolkit, each represented by an been the emergence of a functional tyro- catalysis. (Sometimes, both dual-speci- extant model organism (Figure 2). These sine phosphatase. But why would PTPs ficity phosphatases and classical PTPs stages are representative; we do not arise in the pre-tyrosine kinase world? are referred to as PTPs; here, we use claim to define the exact path of evolution, What functional use and fitness advan- this nomenclature only for the classical but rather focus on identifying the domi- tage would this eraser domain provide in PTP domains that act only on pTyr). The nant classes of stable intermediates that organisms lacking a writer domain? domains of dual-specificity phosphatases can exist in the broader evolutionary land- The answer may lie in the fact that some have a shallower active site than classical scape. Ser/Thr kinase domains, which are more PTPs, which may explain why they can ancient than tyrosine kinases (dating dephosphorylate either Tyr or Thr/Ser PTPs in a Pre-Tyrosine back close to the origins of eukaryotes), residues. In some lineages, dual-speci- Kinase World can carry out sporadic but functionally ficity phosphatases have functionally What came first, TyrK, PTP, or SH2 important phosphorylation
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