FKBPs and the Akt/mTOR pathway

Abstract

PersPeCtives 2366Cell Cycle volume 12 issue 15

Pitfalls of the MTT assay: Direct and off-target effects of inhibitors can result in over/underestimation of cell viability

“…However, FKBP-rapamycin/rapalog complex mediated mechanism of mTOR function inhibition can be de facto the substantial source of the numerous off-target effects. FKBPs (of different molecular mass 12, 12.6, 13, 25, 51, and 52kDa) are the members of the family of peptidylprolyl cis/trans isomerases and strong binders of rapamycin Hausch et al, 2013). Besides their potential to form rapamycininduced ternary complexes with mTOR and hinder mTOR kinase substrate accessibility, the each member of this family has the diverse binding partners (Erlejman et al, 2014;Liu et al, 2013).…”

FKBPs and their role in neuronal signaling

“…To specifically investigate the role of FKBP12 in the brain, Hoefner et al generated brain-specific FKBP12-deficient knockout mice [37]. An unexpected increase in mTOR pathway activity was observed, possibly due to a de-repressed, basal Akt signaling upstream of mTOR [38,39]. Brainspecific FKBP12 deletion also resulted in enhanced hippocampal longterm potentiation (LTP), one of the key molecular mechanisms for the formation of memory.…”

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

“…Recent evidence has also identified rapamycin/sirolimus as being the first drug to extend lifespan in a range of species from yeast to mammals 221,222 , highlighting the potential for drug targeting within this gene family to alleviate the ageing process. Importantly, recent studies have also shown that FK506-binding proteins can modulate Akt-mTOR signalling in the absence of rapamycin 21 .…”

“…PPIases play a significant role by binding to and regulating the mTOR signalling pathway which has very well characterised roles in ageing and age-related diseases 21 . Furthermore, other PPIases such as CypA expression increases with ageing [30][31][32] and suppression of CypB induces cellular senescence 33 and its expression decreases in ageing rats 34 .…”

“…Peptidyl prolyl isomerases (PPIases) also known as immunophillins, are a family of proteins that bind to rapamycinmTOR complexes and regulate the mTOR signaling pathway. These proteins therefore play a significant role in aging and age-related diseases 21 . Therefore, the focus of this review will be on the role of PPIase in aging and age-related diseases: CVDs, T2D, CKD, ND, AMD and cancer.…”