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Fig. 3 | Journal of Translational Medicine

Fig. 3

From: Magnetique: an interactive web application to explore transcriptome signatures of heart failure

Fig. 3

A subset of the CARNIVAL network focusing on the MAPK1 and MAPK3 signaling axes for the DCMvsHCM contrast. Nodes represent members of signaling cascades; round and triangular nodes represent proteins and TFs, respectively. Flat head and arrow head represent interactions that inhibit or activate the downstream elements, respectively. The color of the node represents the inferred protein activity, which ranges from blue (down-regulated) to red (up-regulated). The ​​auxiliary Perturbation node, in the uppermost position, connects all the proteins in the first level of the network. PTPRB, the receptor-type tyrosine-protein phosphatase beta, is likely the primary point for signal transduction. It modulates both MAPK1 (increased activity) and MAPK3 (decreased activity). These protein kinases modulate a series of other factors. Two TFs that are commonly controlled by the MAPK1/MAPK3 signaling axis are MEF2C and EGR1. MEF2C activity is down-regulated by MAPK1 and MAPK3, also known as extracellular signal-regulated kinases (ERKs) 2 and 1, which are central hubs of CARNIVAL networks, with a scaled Kleinberg’s centrality score of 0.356 and 1, respectively. Interestingly, the signs of the inferred activity for these two kinases have been inferred to be opposite to each other: In the DCMvsHCM contrast, MAPK3 appears to be consistently down-regulated while MAPK1 is up-regulated. This suggests a balance between the activities of the two kinases, which can be explained by the differential activity of the PTPRB receptor (receptor-type tyrosine-protein phosphatase beta), which is an upstream regulator for both kinases and is down-regulated. Both kinases differently regulate a series of TFs and their critical roles in heart homeostasis have been recently reviewed by Gilbert and collaborators (via HDAC5) and up-regulated by MAPK3 (via EP300). Conversely, EGR1 activity is controlled by RELA, which is down-regulated by MAPK3 (via SIRT1) and directly up-regulated by MAPK1. In these examples, the activity of TF depends on the balance of the MAPK1/MAPK3 axis.

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