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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Movement
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Disease Progression
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Enzyme Activation
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Humans
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Lysosomes / enzymology
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Matrix Metalloproteinase 2 / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Monomeric GTP-Binding Proteins / metabolism
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Multiprotein Complexes / metabolism*
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Neoplasm Proteins / physiology*
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Neuropeptides / metabolism
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Protein Binding
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Protein Transport
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Protein Tyrosine Phosphatases / physiology*
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Proto-Oncogene Proteins c-akt / metabolism
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Ras Homolog Enriched in Brain Protein
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Signal Transduction
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Stomach Neoplasms / enzymology*
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Stomach Neoplasms / pathology
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TOR Serine-Threonine Kinases / metabolism*
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism
Substances
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Multiprotein Complexes
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Neoplasm Proteins
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Neuropeptides
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RHEB protein, human
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Ras Homolog Enriched in Brain Protein
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TSC2 protein, human
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PTP4A3 protein, human
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Protein Tyrosine Phosphatases
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MMP2 protein, human
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Matrix Metalloproteinase 2
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Monomeric GTP-Binding Proteins