Structural Biochemistry/Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatase

Cellular homeostasis requires balance between phosphorylation catalyzed by protein kinases and dephosphorylation catalyzed by protein phosphatases. Deregulation of this balance leads to pathphysiological states that drive diseases such as cancer, heart disease, and diabetes. The discovery of PHLPP, which stands for Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase, contributes to the cast of phosphate-controlling enzymes in cell signaling. PHLPP isozymes catalyze the dephosphorylation of a conserved regulatory motif, the hydrophobic motif, on the AGC kinases Akt, PKC, and S6 kinase to inhibit cellular proliferation and induce apoptosis.

The frequent deletion of PHLPP in cancer, coupled with development of prostate tumors in mice lacking PHLPP1 identifies PHLPP as an important tumor suppressor. It dephosphorylates a key regulatory site on the C terminus of Akt, the hydrophobic motif, therefore inactivating the kinase.

PHLPP plays an important role in disease. It not only blocks tumorigenesis by inactivation of oncogenic pathways, but also sensitizes cancer cells to chemotherapy. With the loss of PHLPP1, this causes prostate tumors in mice and its genetic deletion or mRNA repression is prevalent in prostate cancer patients.

Reference: Noel A. Warfeland Alexandra Newton from Departments of Pharmacology and Chemistry and Biochemistry, University of California, San Diego