Since the discovery of C-tail phosphorylation of PTEN almost 20 years ago, much progress has been made in understanding its regulatory influences on the cellular function of PTEN. Phosphorylation of Ser380, Thr382, Thr383, and Ser385 drives a PTEN conformational change from an open to closed state where catalytic function is impaired, plasma membrane binding is reduced, and cellular stability is enhanced. Despite these advances, a detailed structural and mechanistic model of how these phosphorylations impact PTEN function is lacking. We discuss here several recent approaches to analyzing PTEN phosphorylation and highlight several insights that have come from this work. We also discuss remaining challenges for the PTEN regulation field and potential directions for future research.
Keywords: Enzymology; PIP3; Phosphorylation; Semisynthesis; Signaling.
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