It was reported that mast cell degranulation is inversely related to the enzymatic activity of $M_2$-type pyruvate kinase ($M_2PK$). This study shows that activation of high-affinity IgE receptor ($Fc{varepsilon}RI$) evokes a sequential dual regulation of $M_2PK$, i.e., an immediate decrement followed by slow phase increment of enzymatic activities. Changes in the activities of $M_2PK$ and mast cell degranulation showed similar time course after antigenic stimulation of $Fc{varepsilon}RI$. The immediate inhibition of $M_2PK$ involved tyrosine phosphorylation, and subsequently led to a cellular accumulation of glycolytic intermediates, including fructose 1,6-biphosphate (FBP), a feedforward activator of $M_2PK$. As the cellular levels of FBP were increased, both the enzymatic acitivity of $M_2PK$ and mast cell degranulation slowly returned to near basal levels. A-Raf, when exogenously introduced into RBL-2H3 cells, phosphorylated $M_2PK$ on the serine residues, elevated enzyme activities of $M_2PK$, and resulted in the inhibition of degranulation. These results suggest that dual regulation of $M_2PK$ which involves the phosphorylation of $M_2PK$ and accumulation of a feedforward activator of $M_2PK$ plays important roles in the control of mast cell degranulation.