Multisite phosphorylation in T cell receptor proximal signalling

Thesis

T cell receptor proximal signalling represents a specific instance of a multisite phosphorylation system. Receptor phosphorylation is regulated by the opposing actions of the kinase LCK, and phosphatases such as CD45 and CD148. Particular phosphoforms recruit the kinase ZAP-70, which once bound, propagates downstream signalling. In this thesis we investigate the functional consequences of multiple phosphorylation sites on the dose-response profiles of receptor phosphorylation. We combine mathematical modelling with cellular reconstitution to assess the effect of multiple modification sites on the potency and sensitivity of receptor phosphorylation. We find that multiple sites enhance the potency of receptor phosphorylation, but do not alter the sensitivity of dose-response profiles. This correlation between the number of sites and response potency is consistent with a mechanism whereby phosphorylation mediates an enhancement in the enzymatic efficiencies of modification.

Authors: Mukhopadhyay, H

• DOI: 10.5287/ora-zg2j2njda
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford