Tyrosine kinase signaling and the emergence of multicellularity - PubMed (original) (raw)

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Tyrosine kinase signaling and the emergence of multicellularity

W Todd Miller. Biochim Biophys Acta. 2012 Jun.

Abstract

Tyrosine phosphorylation is an essential element of signal transduction in multicellular animals. Although tyrosine kinases were originally regarded as specific to the metazoan lineage, it is now clear that they evolved prior to the split between unicellular and multicellular eukaryotes (≈600million years ago). Genome analyses of choanoflagellates and other protists show an abundance of tyrosine kinases that rivals the most complex animals. Some of these kinases are orthologs of metazoan enzymes (e.g., Src), but others display unique domain compositions not seen in any metazoan. Biochemical experiments have highlighted similarities and differences between the unicellular and multicellular tyrosine kinases. In particular, it appears that the complex systems of kinase autoregulation may have evolved later in the metazoan lineage.

Copyright © 2012 Elsevier B.V. All rights reserved.

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Figures

Fig. 1

Fig. 1. Distribution of tyrosine kinases

The eukaryotic tree of life is shown schematically. Species containing eukaryotic-like tyrosine kinases are shown in red.

Fig. 2

Fig. 2. Tyrosine kinases in Monosiga brevicollis

The domain arrangements of representative nonreceptor tyrosine kinases (NRTKs, top) and receptor tyrosine kinases (RTKs, bottom) are shown. Domain predictions are based on the analysis in ref. [15], and a complete list of kinases is given in the supporting information to that paper. Tyrosine kinase catalytic domains are shown in red. At the top left, all Monosiga brevicollis NRTKs with clear metazoan homologs (based on kinase domain sequence similarity) are boxed. Names given in red are NRTKs with domain combinations that have not been observed in metazoans. List of domain abbreviations: Myr, myristoylation sequence; SH3, Src homology 3; SH2, Src homology 2; C2, phospholipid binding domain; PH, pleckstrin homology; PTB, phosphotyrosine binding domain; pseudokin, predicted inactive kinase domain; CH, calponin homology; FYVE, Fab1/YOTB/Vac1/EEA1 zinc-finger domain; LDL, low density lipoprotein receptor motif; tm, transmembrane sequence; SCR, short consensus repeat/complement control protein domain; E, epidermal growth factor repeat; Cys, cysteine-rich region; HYR, repeats similar to hyaline domains; Cupin, barrel-like fold seen in cupin family proteins; LRR, leucine-rich repeats; Fn3, fibronectin type 3 domain.

Fig. 3

Fig. 3. Csk-mediated inhibition of Src

In the active conformation of Src (left), Tyr527 in the C-terminal tail is unphosphorylated, and the SH2 and SH3 domains are disengaged from their intramolecular ligands. The SH3 and SH2 domains bind to ligands on potential substrates, targeting them for phosphorylation by the kinase domain. Phosphorylation of Tyr527 (red circle) produces an intramolecular interaction with the SH2 domain of Src. This interaction, together with an interaction between the SH3 domain and a polyproline type II helix in the linker region, stabilizes the autoinhibited conformation of Src. In the choanoflagellates Monosiga ovata and Monosiga brevicollis, the Csk homologs phosphorylate the residue equivalent to Tyr527, but this does not repress Src activity [16, 29]. The domain structure of Src family kinases and other NRTKs may have arisen initially to fulfill the substrate targeting function [31, 39].

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