Figure 2
From: Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies
RAS Network: cross-links in hypertrophy. The cardiac hypertrophic response implicates signal transduction pathways initiated by ligand-stimulated membrane-bound receptors (RTKs, GPCRs) and biomechanical stress sensors (integrins). Various signaling effectors interact with the RAS/MEK/MAPK pathway. GPCR receptors activate RAS proteins through EPAC, induce release of internal Ca2+ stores and elicit pathological hypertrophy through calcineurin/NFAT. GPCRs also act through ERK activation. GSK3 kinase negatively regulates NFAT and, in turn, is inactivated by the PI3K-AKT pathway stimulated by RAS. Stimuli acting on integrins prompt cardiac hypertrophy through FAK activation and considerable cross-talk with RTK-mediated signaling. In addition, PAK regulates RAF1 activity. All these pathways converge on the modulation of transcriptional factors (MEF2, JUN and GATA4), which induce the expression of genes of the hypertrophic program.