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Comparative expression profiling identifies differential roles for Myogenin and p38? MAPK signaling in myogenesis.

ABSTRACT: Skeletal muscle differentiation is mediated by a complex gene expression program requiring both the muscle-specific transcription factor Myogenin (Myog) and p38? MAPK (p38?) signaling. However, the relative contribution of Myog and p38? to the formation of mature myotubes remains unknown. Here, we have uncoupled the activity of Myog from that of p38? to gain insight into the individual roles of these proteins in myogenesis. Comparative expression profiling confirmed that Myog activates the expression of genes involved in muscle function. Furthermore, we found that in the absence of p38? signaling, Myog expression leads to the down-regulation of genes involved in cell cycle progression. Consistent with this, the expression of Myog is sufficient to induce cell cycle exit. Interestingly, p38?-defective, Myog-expressing myoblasts fail to form multinucleated myotubes, suggesting an important role for p38? in cell fusion. Through the analysis of p38? up-regulated genes, the tetraspanin CD53 was identified as a candidate fusion protein, a role confirmed both ex vivo in primary myoblasts, and in vivo during myofiber regeneration in mice. Thus, our study has revealed an unexpected role for Myog in mediating cell cycle exit and has identified an essential role for p38? in cell fusion through the up-regulation of CD53.

SUBMITTER: Liu QC

PROVIDER: S-EPMC4580549 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Comparative expression profiling identifies differential roles for Myogenin and p38α MAPK signaling in myogenesis.

Liu Qi-Cai QC Zha Xiao-Hui XH Faralli Hervé H Yin Hang H Louis-Jeune Caroline C Perdiguero Eusebio E Pranckeviciene Erinija E Muñoz-Cànoves Pura P Rudnicki Michael A MA Brand Marjorie M Perez-Iratxeta Carol C Dilworth F Jeffrey FJ

Journal of molecular cell biology 20120730 6

Skeletal muscle differentiation is mediated by a complex gene expression program requiring both the muscle-specific transcription factor Myogenin (Myog) and p38α MAPK (p38α) signaling. However, the relative contribution of Myog and p38α to the formation of mature myotubes remains unknown. Here, we have uncoupled the activity of Myog from that of p38α to gain insight into the individual roles of these proteins in myogenesis. Comparative expression profiling confirmed that Myog activates the expre ...[more]

PMID: 22847234

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Project description:The role of TIRAP (toll/interleukin-1 receptor (TIR) domain-containing adapter protein) in macrophage inflammatory signalling has been significantly evolved since its discovery in 2001 due to its dynamic nature and subcellular localization to regulate multiple signaling through several protein-protein interactions (PPIs). Structural analysis of these interactions can reveal a better understanding of their conformational dynamics and the nature of their binding. Tyrosine phosphorylation in the TIR domain of TIRAP is very critical for its function. In toll-like receptor (TLR) 4/2 signalling, Bruton's tyrosine kinase (BTK) and Protein kinase C delta (PKCδ) are known to phosphorylate the Y86, Y106, Y159, and Y187 of TIRAP which is crucial for the downstream function of MAPKs (mitogen-activated protein kinases) activation. The objective of this study is to understand the interaction of TIRAP with p38 MAPK through molecular docking and identify the importance of TIRAP tyrosine phosphorylation in p38 MAPK interaction. In this structural study, we performed an in-silico molecular docking using HADDOCK 2.4, pyDockWEB, ClusPro 2.0, and ZDOCK 3.0.2 tools to unravel the interaction between TIRAP and p38 MAPK. Further, manual in-silico phosphorylations of TIRAP tyrosines; Y86, Y106, Y159, and Y187 was created in the Discovery Studio tool to study the conformational changes in protein docking and their binding affinities with p38 MAPK in comparison to non-phosphorylated state. Our molecular docking and 500 ns of molecular dynamic (MD) simulation study demonstrates that the Y86 phosphorylation (pY86) in TIRAP is crucial in promoting the higher binding affinity (∆Gbind) with p38 MAPK. The conformational changes due to the tyrosine phosphorylation mainly at the Y86 site pull the TIRAP closer to the active site in the kinase domain of p38 MAPK and plays a significant role at the interface site which is reversed in its dephosphorylated state. The heatmap of interactions between the TIRAP and p38 MAPK after the MD simulation shows that the TIRAP pY86 structure makes the highest number of stable hydrogen bonds with p38 MAPK residues. Our findings may further be validated in an in-vitro system and would be crucial for targeting the TIRAP and p38 MAPK interaction for therapeutic purposes against the chronic inflammatory response and associated diseases.

Dataset Information

Comparative expression profiling identifies differential roles for Myogenin and p38? MAPK signaling in myogenesis.

Publications

Comparative expression profiling identifies differential roles for Myogenin and p38α MAPK signaling in myogenesis.

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