title: PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition.
abstract: PRL-3 is a metastasis-associated phosphatase. We and others have shown that its overexpression increases cell motility and invasiveness. These phenotypic changes are reminiscent of the epithelial-mesenchymal transition (EMT) that occurs during embryonic development and oncogenesis. The EMT is a complex process that converts epithelia into migratory mesenchymal cells. We here attempt to unravel the underlying mechanistic basis of these phenomena. HeLa cells transiently expressing EGFP-PRL-3 (HeLa-PRL-3) exhibit reduced levels of paxillin. Similarly, Chinese hamster ovary cells stably expressing myc-PRL-3 (CHO-PRL-3) also show marked reductions in paxillin, phosphorylated paxillin-Tyr(31), and vinculin at focal adhesion complexes and notable reductions in the levels of RhoA-GTP, Rac1-GTP, and filamentous-actin filaments. DLD-1 human colorectal cancer cells engineered to express EGFP-PRL-3 (DLD-1-PRL-3) underwent changes consistent with EMT. In these cells, PRL-3 activates Akt and inactivates glycogen synthase kinase-3beta as assessed by phosphospecific antibodies. PRL-3 up-regulates mesenchymal markers fibronectin and Snail and down-regulates epithelial markers E-cadherin, gamma-catenin (plakoglobin), and integrin beta(3), which are major effectors in the EMT pathway. The changes in these EMT characteristics brought about by PRL-3 can be abrogated by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, implying that PRL-3 acts upstream of PI3K and could play an initiating role to trigger the EMT switch during cancer metastasis. In addition, PRL-3 can down-regulate phosphatase and tensin homologue deleted on chromosome 10, which is an important antagonist of PI3K, further reinforcing PI3K/Akt function in PRL-3-triggered EMT. Catalytically inactive PRL-3 (C104S) was impaired in the above PRL-3-mediated events, indicating that these properties require phosphatase activity. Targeting PRL-3 may thus be a useful strategy to impede cancer cell invasion and metastasis.
authors.affiliation: Institute of Molecular and Cell Biology, Singapore, Singapore.
authors.forename: Haihe
authors.initials: H
authors.lastname: Wang
authors.forename: Samantha Yiling
authors.initials: SY
authors.lastname: Quah
authors.forename: Jing Ming
authors.initials: JM
authors.lastname: Dong
authors.forename: Edward
authors.initials: E
authors.lastname: Manser
authors.forename: Jing Ping
authors.initials: JP
authors.lastname: Tang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D051419:Paxillin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D016596:Vinculin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D009363:Neoplasm Proteins; D051419:Paxillin; C107953:RAC1 protein, human; C488955:VCL protein, human; D016596:Vinculin; D019869:Phosphatidylinositol 3-Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein