Evolution of the phospho-tyrosine signaling machinery in premetazoan lineages

Abstract

Multicellular animals use a three-part molecular toolkit to mediate phospho-tyrosine signaling: Tyrosine kinases (TyrK), protein tyrosine phosphatases (PTP), and Src Homology 2 (SH2) domains function, respectively, as ''writers,'' ''erasers,'' and ''readers'' of phospho-tyrosine modifications. How did this system of three components evolve, given their interdependent function? Here, we examine the usage of these components in 41 eukaryotic genomes, including the newly sequenced genome of the choanoflagellate, Monosiga brevicollis, the closest known unicellular relative to metazoans. This analysis indicates that SH2 and PTP domains likely evolved earliest-a handful of these domains are found in premetazoan eukaryotes lacking tyrosine kinases, most likely to deal with limited tyrosine phosphorylation cross-catalyzed by promiscuous Ser/Thr kinases. Modern TyrK proteins, however, are only observed in two lineages, metazoans and choanoflagellates. These two lineages show a dramatic coexpansion of all three domain families. Concurrent expansion of the three domain families is consistent with a stepwise evolutionary model in which preexisting SH2 and PTP domains were of limited utility until the appearance of the TyrK domain in the last common ancestor of metazoans and choanoflagellates. The emergence of the full threecomponent signaling system, with its dramatically increased encoding potential, may have contributed to the advent of metazoan multicellularity.choanoflagellates ͉ encoding potential ͉ tyrosine kinase ͉ src homology 2 ͉ protein tyrosine phosphatase T yrosine phosphorylation is essential for cell-cell communication in animals, mediating hormone, growth factor, immune, and adhesion-based signaling (1-4). Thus, phosphotyrosine (P-Tyr) signaling has traditionally been linked with metazoan multicellularity (5). Metazoan phospho-tyrosine signaling pathways are built from a three-part system of molecular components: Tyrosine kinases (TyrK) are catalytic domains that add phospho-tyrosine (P-Tyr) modifications, protein tyrosine phosphatases (PTP) are catalytic domains that remove these modifications, and Src Homology 2 (SH2) domains are recognition domains that readout these modifications. These modules play the role of ''writer,'' ''eraser,'' and ''reader,'' respectively, a triad of core functions at the heart of many biological and nonbiological information processing systems (6, 7). By using these three modules in combination, remarkably diverse signaling responses can be generated.A fundamentally important question is how this and other biological reader/writer/eraser information processing systems could have initially evolved, given the highly interdependent function of the individual parts in modern organisms. Because they act as a synergistic system, an incomplete set of components would be deficient in function. What selective advantage could have sustained a stepwise evolutionary path?The P-Tyr signaling machinery presents a particularly interesting case, because it appears to have evolved relatively rece...

Ancient origin of the integrin-mediated adhesion and signaling machinery

“…Similarly, genome data from unicellular metazoan-related lineages is pushing back the times of origin of many gene families formerly believed to be metazoan specific to well into the Proterozoic. Such is the case, for example, of tyrosine kinases (14,50,51), some transcription factors (12,52), membrane-associated guanylate kinases (53), or cadherines (13). The integrin-mediated signaling and adhesion machinery here presented add another striking example to this pattern and suggest that some of these protein families may have emerged even earlier in eukaryote evolution before the divergence of opisthokonts.…”

“…Finally, from our study and that done by Abedin and King (13), we can conclude that the major cell-cell and cell-matrix adhesion mechanisms in metazoans, those mediated by cadherins and integrins, respectively, have a deeper evolutionary origin than previously thought. This adds to the growing evidence that major cell signaling and cell adhesion pathways crucial to metazoan development were present in premetazoan lineages (12,50,51,53). Thus, the answers to what triggered the unicellular-to-multicellular transition that gave rise to metazoans may lie not only in the acquisition of new genes but also in the cooption of ancestral proteins into new functions and the evolution of more complex interactions.…”

Phylogeny of Tec Family Kinases: Identification of a Premetazoan Origin of Btk, Bmx, Itk, Tec, Txk, and the Btk Regulator SH3BP5

“…The evolution of phosphotyrosine signaling suggests that more than 600 million years ago there was a common ancestor for the unicellular choanoflagellates and for multicellular metazoans, which had already developed this ability (King and Carroll, 2001;King et al, 2008;Peterson and Butterfield, 2005;Pincus et al, 2008). In some species, such as in yeast, tyrosine phosphorylation appears at a very low level, most likely due to promiscuity of serine/threonine kinases (Schieven et al, 1986).…”

Clues to the evolution of complex signaling machinery

“…Pincus et al (2) used sequence similarity to identify and enumerate all of the PTKs, PTPs, and SH2 domains in diverse eukaryotic lineages. They found that these genomes could be clearly divided into two groups.…”

“…Many of these activities are regulated by tyrosine phosphorylation, the covalent addition of a phosphate group to tyrosine residues in cell proteins, and the emergence of this signaling mechanism may actually have been a key enabling event in the transition to multicellularity. Two papers in this issue of PNAS take advantage of genome sequences from diverse eukaryotic lineages to address the origins of the tyrosine phosphorylation signaling machinery; they provide tantalizing insights into more general questions of how complex signaling mechanisms might have evolved (1,2).…”