PHLPP phosphatases as a therapeutic target in insulin resistance-related diseases

Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs), originally identified as Akt kinase hydrophobic motif specific phosphatases, have subsequently been shown to regulate several molecules recurring within the insulin signaling pathway. This observation suggests that PHLPP phosphatases may have a clinically relevant role in the pathogenesis of insulin resistance-related diseases and may thus represent suitable targets for the treatment of these conditions.

The literature pertaining to PHLPPs substrates is reviewed herein, along with information on the molecular players involved in regulating the activity and expression of PHLPP phosphatases. In the present review, knowledge of genetic variants in the genes that encode for PHLPP isozymes and the surrounding regulatory regions is also summarized. In addition, data from the studies addressing the role of PHLPPs in insulin resistance-related disorders and from those investigating the possibility to manipulate these phosphatases for therapeutic purposes are presented.

A number of issues should be resolved before PHLPPs are pursued as therapeutic targets including: the mechanisms regulating the specificity of PHLPP isozymes; the possibility of differentially regulating PHLPP family members and the possible impact of PHLPPs modulation on the risk of cancer.