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FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention.

journal contribution
posted on 06.03.2021, 09:11 by Stephanie Annett, Gillian Moore, Tracy Robson
FK506 binding (FKBP) proteins are part of the highly conserved immunophilin family and its members have fundamental roles in the regulation of signalling pathways involved in inflammation, adaptive immune responses, cancer and developmental biology. The original member of this family, FKBP12, is a well-known binding partner for the immunosuppressive drugs tacrolimus (FK506) and sirolimus (rapamycin). FKBP12 and its analog, FKBP12.6, function as cis/trans peptidyl prolyl isomerases (PPIase) and they catalyse the interconversion of cis/trans prolyl conformations. Members of this family uniquely contain a PPIase domain, which may not be functional. The larger FKBPs, such as FKBP51, FKBP52 and FKBPL, contain extra regions, including tetratricopeptide repeat (TPR) domains, which are important for their versatile protein-protein interactions with inflammation-related signalling pathways. In this review we focus on the pivotal role of FKBP proteins in regulating glucocorticoid signalling, canonical and non-canonical NF-κB signalling, mTOR/AKT signalling and TGF-β signalling. We examine the mechanism of action of FKBP based immunosuppressive drugs on these cell signalling pathways and how off target interactions lead to the development of side effects often seen in the clinic. Finally, we discuss the latest advances in the role of FKBPs as therapeutic targets and the development of novel agents for a range of indications of unmet clinical need, including glucocorticoid resistance, obesity, stress-induced inflammation and novel cancer immunotherapy.

Funding

National Children’s Research Centre Crumlin / NCRC | Grant ID: C/18/9

History

Comments

The original article is available at https://www.sciencedirect.com/

Published Citation

Annett S, Moore G, Robson T. FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention. Pharmacology & Therapeutics. 2020;215:107623.

Publication Date

2 July 2020

PubMed ID

32622856

Department/Unit

  • School of Pharmacy and Biomolecular Sciences
  • Irish Centre for Vascular Biology

Research Area

  • Vascular Biology
  • Cancer
  • Immunity, Infection and Inflammation

Publisher

Elsevier

Version

  • Accepted Version (Postprint)

Exports