Figure 1.

Model of the role of MAPK cascades in cardiomyocyte hypertrophy. In response to pressure overload, there is an intramyocardial release of ligands such as endothelin-1 (ET-1), angiotensin II (AngII) and norepinephrine (NE), growth factors such as fibroblast growth factor 1 (FGF1), and cytokines. These extracellular factors bind to and activate transmembrane G protein-coupled receptors (GPCR), receptor tyrosine kinases (RTK) and cytokine receptors (not depicted). Activated transmembrane receptors, in turn, directly activate intracellular signaling proteins, including G proteins (Gq/11) and the Grb2/SoS complex that promote activation of MAPK cascades and the Ca⁺⁺/Calmodulin (CaM)-Calcineurin A (CnA)-NFAT3/4 cascade. Activation of these signaling cascades modulates the growth of cardiomyocytes in the manner depicted. Specifically, ERK MAPK phosphorylates a variety of targets that may contribute to cardiomyocyte growth, including the transcription factors Elk-1 and GATA4, and several proteins that regulate the translational machinery, including tuberin (TSC2 gene product), Mnk1 and p90^RSK. On the other hand, JNK and p38 MAPK phosphorylate NFAT family members, resulting in inhibition of the calcineurin-NFAT hypertrophic pathway.