Fig. 8: A proposed model of both RAF1-dependent cardiac signaling pathways, coupling calcium transients and contraction, and RAF1S257L-enhanced impairment of cardiac contraction, force generation, and calcium transients.
Due to critical ultrastructural defects in the sarcomere that impair the necessary flexibility components, which are crucial stress sensors, and localize relevant MAPK signaling proteins, the RAF1 mutant cardiomyocytes exhibit more MAPK signaling events. The above-mentioned events accompanied by the perturbation of the transcriptional profile of cardiomyocytes resulting from the hyperactivating mutation in RAF1 and further enhanced downstream signaling axes contribute to aberrant calcium transients through altered levels of SERCA and LTCC calcium transporters and PLN as suppressor of SERCA. While affected MYH6 and MYH7 compositions along with other variables contribute towards impaired contractility and force generation, the disease state is further fueled by massively increased pro-hypertrophic signals via NPPB/BNP.
