Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases

Uddipan Sarma, Archana Sareen, Moitrayee Maiti, Vanita Kamat, Raki Sudan, Sushmita Pahari, Neetu Srivastava, Somenath Roy, Sitabhra Sinha, Indira Ghosh, Ajit G. Chande, Robin Mukhopadhyaya, Bhaskar Saha

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Depending on the strength of signal dose, CD40 receptor (CD40) controls ERK-1/2 and p38MAPK activation. At low signal dose, ERK-1/2 is maximally phosphorylated but p38MAPK is minimally phosphorylated; as the signal dose increases, ERK-1/2 phosphorylation is reduced whereas p38MAPK phosphorylation is reciprocally enhanced. The mechanism of reciprocal activation of these two MAPKs remains un-elucidated. Here, our computational model, coupled to experimental perturbations, shows that the observed reciprocity is a system-level behavior of an assembly of kinases arranged in two modules. Experimental perturbations with kinase inhibitors suggest that a minimum of two trans-modular negative feedback loops are required to reproduce the experimentally observed reciprocity. The bi-modular architecture of the signaling pathways endows the system with an inherent plasticity which is further expressed in the skewing of the CD40-induced productions of IL-10 and IL-12, the respective anti-inflammatory and pro-inflammatory cytokines. Targeting the plasticity of CD40 signaling significantly reduces Leishmania major infection in a susceptible mouse strain. Thus, for the first time, using CD40 signaling as a model, we show how a bi-modular assembly of kinases imposes reciprocity to a receptor signaling. The findings unravel that the signalling plasticity is inherent to a reciprocal system and that the principle can be used for designing a therapy.

Original languageEnglish (US)
Article numbere39898
JournalPloS one
Issue number7
StatePublished - Jul 18 2012
Externally publishedYes


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