The role of Bag3 in cell signaling

J Cell Biochem. 2022 Jan;123(1):43-53. doi: 10.1002/jcb.30111. Epub 2021 Jul 23.


Bag3 has been implicated in a wide variety of physiological processes from autophagy to aggresome formation and from cell transformation to survival. We argue that involvement of Bag3 in many of these processes is due to its distinct function in cell signaling. The structure of Bag3 suggests that it can serve as a scaffold that links molecular chaperones Hsp70 and small Hsps with components of a variety of signaling pathways. Major protein-protein interaction motifs of Bag3 that recruit components of signaling pathways are WW domain and PXXP motif that interacts with SH3-domain proteins. Furthermore, Hsp70-Bag3 appears to be a sensor of abnormal polypeptides during the proteotoxic stress. It also serves as a sensor of a mechanical force during mechanotransduction. Common feature of these and probably certain other sensory mechanisms is that they represent responses to specific kinds of abnormal proteins, i.e. unfolded filamin A in case of mechanotransduction or stalled translating polypeptides in case of sensing proteasome inhibition. Overall Hsp70-Bag3 module represents a novel signaling node that responds to multiple stimuli and controls multiple physiological processes.

Keywords: Hippo; heat shock proteins; signaling pathways; stress kinases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy
  • Filamins / metabolism
  • HSP70 Heat-Shock Proteins / chemistry
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Mechanoreceptors / metabolism
  • Mechanotransduction, Cellular*
  • Neoplasms / metabolism*
  • Protein Interaction Domains and Motifs
  • Protein Unfolding
  • Unfolded Protein Response


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BAG3 protein, human
  • FLNA protein, human
  • Filamins
  • HSP70 Heat-Shock Proteins