title: The phosphatase PHLPP1 regulates Akt2, promotes pancreatic cancer cell death, and inhibits tumor formation.
abstract: OBJECTIVE
  The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC).
  
  
  METHODS
  We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis.
  
  
  RESULTS
  PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size.
  
  
  CONCLUSIONS
  PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC.
authors: Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, Los Angeles, California, USA.
authors: Claudia
authors: C
authors: Nitsche
authors: Mouad
authors: M
authors: Edderkaoui
authors: Ryan M
authors: RM
authors: Moore
authors: Guido
authors: G
authors: Eibl
authors: Noriyuki
authors: N
authors: Kasahara
authors: Janet
authors: J
authors: Treger
authors: Paul J
authors: PJ
authors: Grippo
authors: Julia
authors: J
authors: Mayerle
authors: Markus M
authors: MM
authors: Lerch
authors: Anna S
authors: AS
authors: Gukovskaya
mesh_terms: D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000401:mortality; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C494921:AKT2 protein, human; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases