Dual regulation of mast cell degranulation through IgE receptor-mediated modulation of M2-type pyruvate kinase

It was reported that mast cell degranulation isinversely related to the enzymatic activity of M2-typepyruvate kinase (M2PK). This study shows that activationof high-affinity IgE receptor (FceRI) evokes a sequentialdual regulation of M2PK, i.e., an immediate decrementfollowed by slow phase increment of enzymatic activities. Changes in the activities of M2PK and mast cell degranulationshowed similar time course after antigenic stimulationof FceRI. The immediate inhibition of M2PK involvedtyrosine phosphorylation, and subsequently led to a cellularaccumulation of glycolytic intermediates, including fructose1,6-biphosphate (FBP), a feedforward activator ofM2PK. As the cellular levels of FBP were increased, boththe enzymatic acitivity of M2PK and mast cell degranulationslowly returned to near basal levels. A-Raf, whenexogenously introduced into RBL-2H3 cells, phosphorylatedM2PK on the serine residues, elevated enzymeactivities of M2PK, and resulted in the inhibition ofdegranulation. These results suggest that dual regulation ofM2PK which involves the phosphorylation of M2PK andaccumulation of a feedforward activator of M2PK playsimportant roles in the control of mast cell degranulation.