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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.

SUBMITTER: Sarma U

PROVIDER: S-EPMC3399835 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Sarma Uddipan U Sareen Archana A Maiti Moitrayee M Kamat Vanita V Sudan Raki R Pahari Sushmita S Srivastava Neetu N Roy Somenath S Sinha Sitabhra S Ghosh Indira I Chande Ajit G AG Mukhopadhyaya Robin R Saha Bhaskar B

PloS one 20120718 7

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 r ...[more]

PMID: 22815717

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Project description:Current methods of microtia reconstruction include carving an auricular framework from the costal synchondrosis. This requires considerable skill and may create a substantial defect at the donor site.To present a modular component assembly (MCA) approach that minimizes the procedural difficulty with microtia repair and reduces the amount of cartilage to a single rib.Ex vivo study and survey. A single porcine rib was sectioned into multiple slices using a cartilage guillotine, cut into components outlined by 3-dimensional printed templates, and assembled into an auricular scaffold. Electromechanical reshaping was used to bend cartilage slices for creation of the helical rim. Chondrocyte viability was confirmed using confocal imaging. Ten surgeons reviewed the scaffold constructed with the MCA approach to evaluate aesthetics, stability, and clinical feasibility. The study was conducted from June 5 to December 18, 2014.The primary outcome was creation of a modular component assembly method that decreases the total amount of rib needed for scaffold construction, as well as overall scaffold acceptability. The surgeons provided their assessments through a Likert-scale survey, with responses ranging from 1 (disagree with the statement) to 5 (agree with the statement). Thus, a higher score represents that the surgeon agrees that the scaffold is structurally and aesthetically acceptable and feasible.An auricular framework with projection and curvature was fashioned from 1 rib. The 10 surgeons who participated in the survey indicated that the MCA scaffold would meet minimal aesthetic and anatomic acceptability. When embedded under a covering, the region of the helix and antihelix of the scaffold scored significantly higher on the assessment survey than that of an embedded alloplast implant (mean [SD], 4.6 [0.97] vs 3.5 [1.27]; P?=?.007). Otherwise, no significant difference was found between the embedded MCA and alloplast implants (4.42 [0.48] vs 3.87 [0.41]; P?=?.13). Cartilage prepared with electromechanical reshaping was viable.This study demonstrates that 1 rib can be used to create an aesthetic and durable framework for microtia repair. Precise assembly and the ability to obtain thin, uniform slices of cartilage were essential. This cartilage-sparing MCA approach may be an alternative to classic techniques.NA.

Dataset Information

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

Publications

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

Similar Datasets

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