Coevolution of the domains of cytoplasmic tyrosine kinases

Many signaling molecules are multidomain proteins that have other domains i n addition to the catalytic kinase domain. Protein tyrosine kinases almost without exception contain Src homology 2 (SH2) and/or SH3 domains that can interact with other signaling proteins. Here, we studied evolution of the t yrosine kinases containing SH2 and/or SH3 and kinase domains. The three dom ains seem to have duplicated together, since the phylogenetic analysis usin g parsimony gave almost identical evolutionary trees for the separate domai ns and the multidomain complexes. The congruence analysis of the sequences for the separate domains also suggested that the domains have coevolved. Th ere are several reasons for the domains to appear in a cluster. Kinases are regulated in many ways, and the presence of SH2 and SH3 domains at proper positions is crucial. Because all three domains can recognize different par ts of ligands and substrates, their evolution has been interconnected. The reasons for the clustering and coevolution of the three domains in protein tyrosine kinases (PTKs) are discussed.