The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal.
Activation of cell-surface receptors stimulates generation of intracellular signals that, in turn, direct the cellular response. However, mechanisms that ensure combinatorial control of these signaling events are not well understood. We show here that the Ca2+ and reactive oxygen intermediates generated upon BCR activation rapidly engage in a cooperative interaction that acts in a feedback manner to amplify the early signal generated. This cooperativity acts by regulating the concentration of the oxidant produced. The latter exerts its influence through a pulsed inactivation of receptor-coupled phosphatases, where the amplitude of this pulse is determined by oxidant concentration. The extent of phosphatase inhibition, in turn, dictates what proportion of receptor-proximal kinases are activated and, as a result, the net strength of the initial signal. It is the strength of this initial signal that finally determines the eventual duration of BCR signaling and the rate of its transmission through downstream pathways.
Singh
Dinesh Kumar
DK
Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Dehli, India.
Kumar
Dhiraj
D
Siddiqui
Zaved
Z
Basu
Sandip Kumar
SK
Kumar
Vikas
V
Rao
Kanury V S
KV
D002118:Calcium / Q000378:metabolism*; D000074623:Dual Oxidases; D025461:Feedback, Physiological / Q000502:physiology; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D005420:Flavoproteins; D017382:Reactive Oxygen Species; D011947:Receptors, Antigen, B-Cell; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium