title: Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression.
abstract: Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.
authors: The Beatson Institute for Cancer Research, Glasgow, United Kingdom.
authors: Rachana
authors: R
authors: Patel
authors: Meiling
authors: M
authors: Gao
authors: Imran
authors: I
authors: Ahmad
authors: Janis
authors: J
authors: Fleming
authors: Lukram B
authors: LB
authors: Singh
authors: Taranjit Singh
authors: TS
authors: Rai
authors: Arthur B
authors: AB
authors: McKie
authors: Morag
authors: M
authors: Seywright
authors: Robert J
authors: RJ
authors: Barnetson
authors: Joanne
authors: J
authors: Edwards
authors: Owen J
authors: OJ
authors: Sansom
authors: Hing Y
authors: HY
authors: Leung
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D059585:G1 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D046888:Tissue Array Analysis; D047368:Tumor Burden
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C485561:SPRY2 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human