![]() Recent advances in detecting lipidated proteins by proteomic and targeted approaches have revealed that lipidation of signaling proteins is essential for regulating a wide variety of signaling pathways. Such modifications regulate protein localization and function in many signaling processes. Protein lipidation is the cotranslational or posttranslational covalent addition of a variety of lipids, including fatty acids, isoprenoids, and cholesterol, to target proteins. Recently, it has been found that multiple proteins which regulate apoptotic calcium release in both the intrinsic and extrinsic pathways are subject to lipidation. Calcium also contributes to the progression of the extrinsic pathway ( 18– 21) however, this is less well understood. ![]() ![]() Thus, in type II cells the extrinsic pathway converges with the intrinsic pathway at the mitochondria. Cell which do not engage the mitochondrial pathway are called “type I” cells, and those which lead to mitochondrial permeabilization are called “type II” cells ( 17). Truncated Bid leads to mitochondrial permeabilization and release of proapoptotic proteins ( 16). Caspase 8/10 can directly cleave and activate effector caspases and/or cleave the proapoptotic Bcl-2 family protein Bid. Ligand binding to the death receptor results in the activation of the initiator caspases 8 and 10 ( 13– 15). The extrinsic apoptosis pathway is activated by ligand binding to death receptors of the tumor necrosis factor-α (TNFα) superfamily. Elevated cytosolic calcium then contributes to the apoptotic program in a multitude of ways including mitochondrial permeabilization and further activation of proapoptotic Bcl-2 proteins ( 12). In addition to their roles in mitochondrial membrane permeabilization, Bcl-2 family proteins are also essential and direct regulators of intracellular calcium during apoptosis by binding to a surprising variety of channels, pumps, and exchangers ( 3– 11). The intrinsic apoptosis pathway is activated by cellular stress and leads to Bcl-2 protein activation, mitochondrial membrane permeabilization, and release of proapoptotic proteins ( 1, 2). In this review, we will discuss the role of protein lipidation in regulating apoptotic calcium signaling with direct therapeutic relevance to cancer.Īpoptotic cell death is important for embryonic development and tissue homeostasis, and dysfunction of this pathway can contribute to various disease states, including cancer. Although classically thought of as a static modification, rapid and reversible protein acylation has emerged as a new signaling paradigm relevant to many pathways, including calcium release and cell death. Recently, it has been shown that protein lipidation is a potent regulator of apoptotic signaling. Although we have a thorough understanding of how downstream elevations in cytosolic and mitochondrial calcium contribute to cell death, it is much less clear how calcium channels are activated upstream of the apoptotic stimulus. A large body of evidence indicates that defects in this pathway contribute to cancer development. One of the most proximal events leading to cell death is activation of plasma membrane and endoplasmic reticulum-resident calcium channels. Department of Biochemistry and Molecular Biology, McGovern Medical School, UTHealth, Houston, TX, United StatesĬalcium is a critical regulator of cell death pathways. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |