Phosphotyrosine recognition domains: the typical, the atypical and the versatile

Intracellular communication is transmitted via networks of molecules that execute information transfer using protein-mediated interactions. Post-translational modifications (PTMs) such as protein phosphorylation, acetylation, methylation and ubiquitination confer spatiotemporal dynamics to cell signaling [1]. Among these PTMs, the tyrosine phosphorylation signaling system in eukaryotes, especially in mammalian species, has been extensively studied owing to its importance in numerous cellular functions including differentiation, proliferation, motility and apoptosis as well as its therapeutic potential. In particular, mutations and aberrant expression of kinases are frequently associated with tumourigenesis [2,3].Signaling proteins often possess a cassette-like architecture made up of catalytic domains and/or protein interaction modules [4]. One important group of protein-protein interaction modules are the autonomous domains that recognize phosphorylated tyrosine (pTyr) residues at specific sites on their target molecules [5]. These pTyr-binding protein modules and their targets are a part of an elaborate pTyr signaling system that consists of three major components that help relay molecular messages [6]. The pTyr signaling system is activated when a stimulus reaches catalytic proteins that act as “writers” of phosphorylation, the protein tyrosine kinases (PTKs). Most PTKs are phosphorylated on themselves to attain an active state, and subsequently phosphorylate other substrate proteins. A second group of proteins that contain modular domains are capable of recognizing or “reading” this phospho-modification information and thereby linking the kinase signal to downstream molecules. The phosphorylation can be subsequently “erased” by a third group of proteins, the protein tyrosine phosphatases (PTPs), therefore terminating the signal [7,8].The human genome harbours 90 PTKs [9], hundreds of pTyr-recognition domains that include 121 members of the Src homology 2 (SH2) d