title: PRL-3 activates mTORC1 in Cancer Progression.
abstract: PRL-3, a metastasis-associated phosphatase, is known to exert its oncogenic functions through activation of PI3K/Akt, which is a key regulator of the rapamycin-sensitive mTOR complex 1 (mTORC1), but a coherent link between PRL-3 and activation of mTOR has not yet been formally demonstrated. We report a positive correlation between PRL-3 expression and mTOR phospho-activation in clinical tumour samples and mouse models of cancer and demonstrate that PRL-3 increased downstream signalling to the mTOR substrates, p70S6K and 4E-BP1, by increasing PI3K/Akt-mediated activation of Rheb-GTP via TSC2 suppression. We also show that PRL-3 increases mTOR translocation to lysosomes via increased mTOR binding affinity to Rag GTPases in an Akt-independent manner, demonstrating a previously undescribed mechanism of action for PRL-3. PRL-3 also enhanced matrix metalloproteinase-2 secretion and cellular invasiveness via activation of mTOR, attributes which were sensitive to rapamycin treatment. The downstream effects of PRL-3 were maintained even under conditions of environmental stress, suggesting that PRL-3 provides a strategic survival advantage to tumour cells via its effects on mTOR.
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore.
authors.forename: Zu
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.
authors.forename: Abdul Qader Omer
authors.initials: AQ
authors.lastname: Al-Aidaroos
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.
authors.forename: Hiu Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.
authors.forename: Shu Dong
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.
authors.forename: Youbin
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore.
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Republic of Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020559:Monomeric GTP-Binding Proteins