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

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, whi...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-08, Vol.131 (16)
Main Authors: Kirk, Jonathan A, Cheung, Joseph Y, Feldman, Arthur M
Format: Article
Language:English
Subjects:
Apoptosis
Binding proteins
Cancer
Care and treatment
Development and progression
Genetic aspects
Health aspects
Heart diseases
Methods
Molecular targeted therapy
Review
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Summary: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 [beta]-adrenergic receptor with the L-type [Ca.sup.2+] 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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI149415