Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease
Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman
Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman
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Review

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Abstract

Bcl2-associated athanogene-3 (BAG3) is expressed ubiquitously in humans, but its levels are highest in the heart, the skeletal muscle, and the central nervous system; it is also elevated in many cancers. BAG3’s diverse functions are supported by its multiple protein-protein binding domains, which couple with small and large heat shock proteins, members of the Bcl2 family, other antiapoptotic proteins, and various sarcomere proteins. In the heart, BAG3 inhibits apoptosis, promotes autophagy, couples the β-adrenergic receptor with the L-type Ca2+ channel, and maintains the structure of the sarcomere. In cancer cells, BAG3 binds to and supports an identical array of prosurvival proteins, and it may represent a therapeutic target. However, the development of strategies to block BAG3 function in cancer cells may be challenging, as they are likely to interfere with the essential roles of BAG3 in the heart. In this Review, we present the current knowledge regarding the biology of this complex protein in the heart and in cancer and suggest several therapeutic options.

Authors

Jonathan A. Kirk, Joseph Y. Cheung, Arthur M. Feldman

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Figure 2

Diverse cellular roles of BAG3.

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Diverse cellular roles of BAG3. (A) BAG3 regulates contractility in adul...
(A) BAG3 regulates contractility in adult ventricular myocytes, colocalizing with Na+-K+/ATPase and the L-type Ca2+ channel in the sarcolemma and the transverse tubules (t-tubules). Figure 3 shows BAG3’s function in the sarcomere in more detail. (B) BAG3 also plays a central role in autophagy and mitophagy, creating a complex including hsp70 and hspB8 to deliver ubiquitinated, misfolded proteins to the phagophore. This process is both specific and selective. BAG3 is also involved in the maturation of the phagophore into the autophagosome, through its interaction with synaptopodin-2 (SYNPO2) and its associated proteins. BAG3 also serves as an anchoring point for the dynein motor pathway, an intracellular transport system that moves cargo toward the minus ends of microtubules, where they are packaged into perinuclear aggresomes for eventual removal from the cell. (C) Finally, BAG3 couples to Bcl2 to limit the mitochondria-dependent apoptosis pathway.