Dual regulation of mast cell degranulation through IgE receptor-mediated modulation of M₂-type pyruvate kinase.
It was reported that mast cell degranulation is inversely related to the enzymatic activity of M₂-type pyruvate kinase (M₂PK). This study shows that activation of high-affinity IgE receptor (FcεRI) evokes a sequential dual regulation of M₂PK, i.e., an immediate decrement followed by slow phase increment of enzymatic activities. Changes in the activities of M₂PK and mast cell degranulation showed similar time course after antigenic stimulation of FcεRI. The immediate inhibition of M₂PK involved tyrosine phosphorylation, and subsequently led to a cellular accumulation of glycolytic intermediates, including fructose 1,6-biphosphate (FBP), a feedforward activator of M₂PK. As the cellular levels of FBP were increased, both the enzymatic acitivity of M₂PK and mast cell degranulation slowly returned to near basal levels. A-Raf, when exogenously introduced into RBL-2H3 cells, phosphorylated M₂PK on the serine residues, elevated enzyme activities of M₂PK, and resulted in the inhibition of degranulation. These results suggest that dual regulation of M₂PK which involves the phosphorylation of M₂PK and accumulation of a feedforward activator of M₂PK plays important roles in the control of mast cell degranulation.
Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-ju, 500-757, Korea.
Mei
M
Zheng
Dong-Im
DI
Cho
Hang Thi
HT
Le
Seung Hoon
SH
Cheon
Kyeong-Man
KM
Kim
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D045163:Antibodies, Phospho-Specific; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005635:Fructosediphosphates / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics / Q000378:metabolism; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017455:Receptors, IgE / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D045163:Antibodies, Phospho-Specific; C553474:FCER1A protein, rat; D005635:Fructosediphosphates; D017455:Receptors, IgE; D011994:Recombinant Proteins; D007073:Immunoglobulin E; D012694:Serine; D011770:Pyruvate Kinase; D048491:Proto-Oncogene Proteins A-raf; C029063:fructose-1,6-diphosphate