Research Summary

Understanding the Biochemical and Structural Basis of Signaling Modularity of Kinases in Their Biological Context

The human genome encodes more than 500 protein kinases, which provide the regulatory framework for most signaling pathways in eukaryotic cells. They create modified chemical entities by adding phosphate groups to amino acids that provide altered functionality to protein substrates. Stringent regulation of kinase-activities is critical to proper functioning of cellular processes making protein kinases important drug targets. Many of them show signaling modularity entailing both beneficial and harmful outcomes, depending upon the situation. Indiscriminate inhibition of these activities by active-site directed drugs often lead to deleterious side-effects. It is important to investigate the mechanistic details of their activation and spatio-temporal regulations to fully realize the scope of controlling them in a manner beneficial for the organism.

In my laboratory, a unique combination of biochemical, biophysical, genetic and structural biology approaches will be adopted to investigate regulatory mechanisms critical for kinase-signaling modularity in a context dependent manner. Signaling modularity is dictated by choice of substrates, cognate-binding partners, subcellular localization and post-translational modifications of the kinase itself. Systematic investigation of kinase-signaling complexes at different stages (pre- and post-stimulation) of action might enable us to modulate them more appropriately in a given patho-physiological condition without affecting their role in normal cell physiology.


 

 

Figure Legend: Delicate balance between protein kinase and phosphatase activity is crucial, lack of which often causes havoc. A single kinase may show signalling modularity depending upon the nature of the signal.