Overview

 

Approximately 1.7% of our genome encodes for more than 500 different kinases and they have been found to be essential in nearly every aspect of cellular function.

 

Phosphorylation

The role of kinases is to catalyse the reaction of phosphorylation. Phosphorylation involves the transfer of a phosphate group to the hydroxy side chain on certain amino acids.

The phosphorylation reaction:

phosphotyrosine reaction

 

This phosophorylation can drive many changes in the cell. The reaction is often a major mechanism in signalling cascades, as it has been described as a 'molecular switch' either activating or inactivating the target substrates. In this way a signal molecule may activate one protein which can activate another which may activate another and so on, until a response is produced for example the a change in transcription. Phosphorylation may produce this activity due to a conformational change in the protein which results from the fact that phosphate carries negative charges and this could induce the clustering of positively charged amino acids in the protein. Phosphorylation can also produce binding sites for other proteins especially those with src homology 2 (SH2) and phosphotyrosine bind (PTB) domains.

The phosphorylation reaction is a reversible reaction and the removal of a phosphate from tyrosine is catalysed by proteins called tyrosine phosphatases. There are thirty different tyrosine phosphatases and they can be either transmembrane or cytoplasmic proteins. SHP1 and SHP2 are two types of phosphatases that contain SH2 domains.

 

 

Tyrosine Kinases

As the name suggests, tyrosine kinases are kinases that covalently attach phosphates to tyrosine amino acids in specific sequences. These specific sequences are called consensus sequences and are recognised by specific kinases.

For example Src kinase will phosphorylate a tyrosine in this sequence:

 

Lysine-Arginine-x-x-x-Aspartic acid-Glutamate-x-x-Tyrosine

 

All protein kinases have evolved from a common ancestral gene and as such, they all have a highly conserved catalytic domain responsible for the phosphor-transfer reaction. This high degree of conservation suggests that kinases all work via the same mechanism and that any evolutionary change to structure has only affected the variety of proteins they can target. Tyrosine kinases were the latest kinases to evolve, branching off from serine/threonine kinases in the evolutionary tree.

Tyrosine kinases were first discovered by Tony Hunter in 1979, before this phosphorylation was thought to only occur on serine and threonine. There are now 90 tyrosine kinases that have been identified and these are split into two groups:

     

  1. Receptor Protein Tyrosine Kinases

    There are 58 Receptor protein tyrosine kinases which include the epidermal growth factor receptors (EGFR) and these have many roles in cell growth, proliferation, metabolism, angiogensis and cell survival.

  2. Non Receptor Protein Tyrosine Kinases

    The src kinase is one of the 32 different non receptor protein tyrosine kinases and were the first tyrosine kinases to be discovered. Many of these tyrosine kinases are linked to receptors and can act in similar pathways to the receptor tyrosine kinases.