Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases.
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...
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2012
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oai:doaj.org-article:ef888165a46a4cb6b4641cee1ce836892021-11-18T07:12:06ZModeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases.1932-620310.1371/journal.pone.0039898https://doaj.org/article/ef888165a46a4cb6b4641cee1ce836892012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22815717/?tool=EBIhttps://doaj.org/toc/1932-6203Depending 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.Uddipan SarmaArchana SareenMoitrayee MaitiVanita KamatRaki SudanSushmita PahariNeetu SrivastavaSomenath RoySitabhra SinhaIndira GhoshAjit G ChandeRobin MukhopadhyayaBhaskar SahaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e39898 (2012) |
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| topic |
Medicine R Science Q |
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Medicine R Science Q 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 Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Uddipan Sarma |
| title |
Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| title_short |
Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| title_full |
Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| title_fullStr |
Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| title_full_unstemmed |
Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases. |
| title_sort |
modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of cd40 receptor activated kinases. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/ef888165a46a4cb6b4641cee1ce83689 |
| work_keys_str_mv |
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| _version_ |
1718423827018416128 |