Prolyl cis/trans isomerase signalling pathways in cancer

It is an emerging view that in many cases cell signalling relies on slow conformational interconversions of the backbone of key proteins as exemplified by the prolyl cis/trans isomerization, and that prolyl cis/trans isomerases (PPIases), such as cyclophilins, FK506-binding proteins and the parvulin-like Pin1, serve to integrate temporally and spatially protein conformers with signalling events. The causal relationship between prolyl cis/trans isomerization catalysis, malignant transformation and tumour progression is not yet fully understood because of the pleiotropic biochemical effects characterizing these enzymes. However, recent studies on the role of cyclophilins and Pin1 indicate that PPIases utilize isomerization catalysis on client proteins under physiological and pathophysiological conditions. This knowledge could offer new cancer intervention strategies based on the development of isoenzyme-specific, tissue-specific and organelle-specific PPIase inhibitors.

► Catalytic function of prolyl cis/trans isomerases controls client protein activity. ► Combined data on CypA and Pin1 expression in tumours can yield improved prognostic information. ► The tumour suppressor p53 belongs to CypA interacting proteins. ► Pin1 is a regulator of post-translational modifications of protein substrates.