Abstract

Protein-tyrosine kinases (PTKs) are essential regulators of intracellular signal-transduction pathways in eukaryotes. Tyrosine phosphorylation plays an important role in the control of several cellular processes such as cell proliferation, cell migration, differentiation, immune response, and cell cycle.
Their activity is normally tight control and regulated. Perturbation of the PTK signaling by mutation and other genetic alterations result in deregulated kinase activity and malignant transformation.
The mechanism of substrate recognition by the PTKs has been one of the major challenges in phosphorylation research over the years.
Peptide library approaches have provided some insight about the role of amino acid immediately surrounding Tyr phosphorylation sites and it has been shown that the specificity of PTKs is dominated by acidic or hydrophobic residues adjacent to the phosphorylated residue (Sonyang, 1999) Based on a lager set of experimentally verified phosphorylation sites, Bloom et al. (1999) found that some aminoacids were not present in some positions e.g. tryptophan was never found in position -5 to -1. Similarly, cysteine was never found at position -2 and -1, while methionine was always absent in position -2.
Recently, numerous studies have revealed that the local amino acid sequence is certainly not the sole determinant of substrate specificity but other several factor, including local structure, protein-protein interaction and surface accessibility, also play a main role.