title: Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases.
abstract: 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.
authors: National Centre for Cell Science, Ganeshkhind, Pune, India.
authors: Uddipan
authors: U
authors: Sarma
authors: Archana
authors: A
authors: Sareen
authors: Moitrayee
authors: M
authors: Maiti
authors: Vanita
authors: V
authors: Kamat
authors: Raki
authors: R
authors: Sudan
authors: Sushmita
authors: S
authors: Pahari
authors: Neetu
authors: N
authors: Srivastava
authors: Somenath
authors: S
authors: Roy
authors: Sitabhra
authors: S
authors: Sinha
authors: Indira
authors: I
authors: Ghosh
authors: Ajit G
authors: AG
authors: Chande
authors: Robin
authors: R
authors: Mukhopadhyaya
authors: Bhaskar
authors: B
authors: Saha
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D025461:Feedback, Physiological; D018320:Leishmania major / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019013:CD40 Antigens; D011494:Protein Kinases