Regulation of Kinases: 1 Billion Years of Evolution

Protein phosphorylation is an essential regulatory mechanism that affects all aspect of cellular life from division and growth to aging and death. Misregulation of the signaling cascades leads to severe detrimental effects, and in humans often associated with cancer and other diseases. Phosphorylation is performed by a class of protein called kinases. Activation and deactivation of kinases is normally under tight control and is regulated via different mechanisms that are incredibly complex. In this work we combine phylogenetic resurrection techniques with biophysical and chemical approaches to analyze the regulatory mechanisms of modern tyrosine oncokinases Src and Abl, their common ancestor and the common ancestors between several other families of tyrosin kinases. Our results show how the regulatory elements appeared and developed throughout the evolution enabling selective regulation of complex modern cascades.