Deciphering the Role of PKC in Calpain-CAST System Through Formal Modeling Approach

Calcium-activated calpain has critical role in a variety of calcium regulated processes. Calcium activates two other proteins, Calpastatin (CAST) and Protein Kinase C (PKC) to make a regulatory network which is pivotal in cell physiology. CAST binds with calpain to form complex for hampering its hyperactivation. PKC phosphorylates CAST while calpain proteolyzes active PKC and increases calcium influx. Based on biological knowledge, a qualitative (discrete) model is constructed that provides new insights into the dynamics of calpain-CAST and PKC relationship. The model predicts that PKC maintains calpain-CAST complex by interacting with both active calpain and CAST. It is also observed that in physiological condition, there is a homeostatic behavior between calcium, CAST and PKC. Some significant discrete cycles are also identified by analyzing betweenness centralities of the discrete states. There is one stable state in the model in which calpain and calcium are hyperactivated while CAST and PKC are inactivated. The model is validated through the stochastic Petri Net model that further reveals its quantitative dynamical behaviors. Physiology is perturbed by hyperactivation of calpain which results in the deregulation of homeostasis. Both models suggest that inhibition of calpain by CAST is a better therapeutic strategy which requires healthy assistance from PKC. In conclusion, homeostasis of calcium, CAST and PKC is pivotal for a healthy state.