Phosphorylation-Specific Prolyl Isomerase Pin1 as a new Diagnostic and Therapeutic Target for Cancer

Abstract

Proline directed phosphorylation is a key regulatory mechanism controlling the function of fundamental proteins involved in cell proliferation and oncogenic transformation. Recently, the identification of the phosphorylation dependent prolyl isomerase Pin1 has uncovered a distinct regulatory mechanism controlling protein function. Specifically, Pin1 controls the conversion of peptidyl proline bond conversion from cis to trans, only when the preceding serine or threonine is phosphorylated. The intrinsic inter-conversion of such bonds is rather slow and is further inhibited by phosphorylation. As a consequence catalysis by Pin1 is required to overcome this restriction. Importantly, structural evidence has now demonstrated that Pin1-catalyzed prolyl isomerization can have significant effects on the global structure of substrate proteins. Furthermore, Pin1 overexpression is found in several types of cancer where it functions to not only promote tumorigenesis induced by oncogenes such as Ras and Neu, but also to regulate molecules that facilitate persistent proliferative capacity. Consequently, Pin1-mediated phosphorylation-dependent isomerization represents a unique regulatory mechanism in cell signaling whose deregulation during tumorigenesis adds to the pro-proliferative capacity of tumor cells and therefore Pin1 represents a novel tumor marker and potential therapeutic target.