Predictive Model of Lymphocyte-Specific Protein Tyrosine Kinase (LCK) Autoregulation

Jennifer A. Rohrs, Pin Wang, Stacey D. Finley

Lymphocyte-specific protein tyrosine kinase (LCK) is a key activator of T cells; however, little is known about the specific autoregulatory mechanisms that control its activity. We have constructed a model of LCK autophosphorylation and phosphorylation by the regulating kinase CSK. The model was fit to existing experimental data in the literature that presents an in vitro reconstituted membrane system, which provides more physiologically relevant kinetic measurements than traditional solution-based systems. The model is able to predict a robust mechanism of LCK autoregulation. It provides insights into the molecular causes of key site-specific phosphorylation differences between distinct experimental conditions. Probing the model also provides new hypotheses regarding the influence of individual binding and catalytic rates, which can be tested experimentally. This minimal model is required to elucidate the mechanistic interactions of LCK and CSK and can be further expanded to better understand T cell activation from a systems perspective. Our computational model enables the evaluation of LCK protein interactions that mediate T cell activation on a more quantitative level, providing new insights and testable hypotheses.