title: Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling.
abstract: Precise balance between phosphorylation, catalyzed by protein kinases, and dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Deregulation of this balance leads to pathophysiological states that drive diseases such as cancer, heart disease, and diabetes. The recent discovery of the PHLPP (pleckstrin homology domain leucine-rich repeat protein phosphatase) family of Ser/Thr phosphatases adds a new player 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, as well as an inhibitory site on the kinase Mst1, to inhibit cellular proliferation and induce apoptosis. The frequent deletion of PHLPP in cancer, coupled with the development of prostate tumors in mice lacking PHLPP1, identifies PHLPP as a novel tumor suppressor. This minireview discusses the structure, function, and regulation of PHLPP, with particular focus on its role in disease.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Noel A
authors.initials: NA
authors.lastname: Warfel
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000201:enzymology / Q000235:genetics; D005260:Female; D006331:Heart Diseases / Q000201:enzymology / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D025521:Tumor Suppressor Proteins; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C095566:STK4 protein, human; C400601:PHLPP1 protein, human; C519282:PHLPP1 protein, mouse