Figure 1: Cell death pathways that normally underlie cellular apoptosis and necrosis. Apoptosis consists of an extrinsic pathway mediated by death receptors such as the tumor necrosis factor receptor (TNFR) and Fas ligand receptor, which induces DISC formation to initiate caspase-8 cleavage, leading to caspase-3 activation. Activated caspase-8 can also cleave Bid, which then interacts with the mitochondria to induce outer membrane permeability and cytochrome c (CytC) release. The second arm of apoptosis is the intrinsic pathway that relies on mitochondrial-dependent killing initiated by ROS (reactive oxygen species), calcium, and hypoxic stimuli that results in cytochrome c release and apoptosome formation. The apoptosome consists of caspase-9, Apaf1, and cytochrome c, which induces caspase-3 cleavage and activation. Apoptosis also results in release of Smac, which further permits caspase activation and release of DNA fragmentation facilitators that affect the nucleus. The Bcl2 family members Bax and Bak are the primary regulators of the intrinsic pathway. Necrosis can be programmed by induction of the mitochondrial pore, leading to increased permeability after stimulation by ROS, calcium, and other stimuli. Cyclophilin D (CypD) is the only known bona fide component of this inducible pore in the mitochondria that programs necrosis.
Image: Jeffery Molkentin
Figure 2: Schematic of the intracellular signaling pathways that participate in the regulation of hypertrophy and/or disease of the heart.
Jeffery Molkentin
Figure 3: Fibroblasts transdifferentiate into myofibroblasts in response to cytokines, where they mediate tissue repair and fibrosis. We showed that the Ca2+ channel TRPC6 provides Ca2+ to activate phosphatase calcineurin, which is then necessary and sufficient for myofibroblast differentiation through a signaling pathway that uses noncanonical transforming growth factor β (TGFβ) to mobilize p38 mitogen-activated protein kinase (MAPK) and the transcription factor SRF.
(EMC = extracellular matrix)
Jeffery Molkentin. See also Davis, J., Burr, A.R., Davis, G.F., Birnbaumer, L., and Molkentin, J.D. 2012. Developmental Cell 23:705-715
Figure 4: Thrombospondin (Thbs) proteins are induced during tissue damage or active remodeling in coordination with the endoplasmic reticulum (ER) stress response. We recently showed a novel function for Thbs proteins as ER resident effectors of an adaptive ER stress response. Thbs proteins bind the ER luminal domain of activating transcription factor 6α (Atf6α) to promote its processing in the Golgi and subsequent nuclear shuttling and the adaptive ER stress response. This function of Thbs secondarily affects total vesicular processing and enhances the production and secretion of many proteins, including those in the extracellular matrix (ECM) to collectively provide protection and greater resistance to various disease responses associated with ER stress and unfolded protein accumulation.
Jeffery Molkentin. See also Lynch, J.M., Maillet, M., Vanhoutte, D., Schloemer, A., Sargent, M.A., Blair, N.S.,Lynch, K.A., Okada, T., Aronow, B.J., Osinska, H., Prywes, R., Lorenz, J.N., Mori, K., Lawler, J., Robbins, J., and Molkentin, J.D. 2012. Cell 149:1257-1268.
