PRL-3 activates mTORC1 in Cancer Progression

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.

[1]  Mu Wang,et al.  Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Prometastatic Signal Transduction* , 2013, Molecular & Cellular Proteomics.

[2]  Q. Zeng,et al.  Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. , 2013, The Journal of clinical investigation.

[3]  K. Guan,et al.  Amino acid signalling upstream of mTOR , 2013, Nature Reviews Molecular Cell Biology.

[4]  C. Pallen,et al.  PRL PTPs: mediators and markers of cancer progression , 2008, Cancer and Metastasis Reviews.

[5]  Chang Hwa Jung,et al.  mTOR regulation of autophagy , 2010, FEBS letters.

[6]  J. Li,et al.  PCBP1 suppresses the translation of metastasis-associated PRL-3 phosphatase. , 2010, Cancer cell.

[7]  D. Guertin,et al.  Rictor, a Novel Binding Partner of mTOR, Defines a Rapamycin-Insensitive and Raptor-Independent Pathway that Regulates the Cytoskeleton , 2004, Current Biology.

[8]  G. Homanics,et al.  Protein-tyrosine Phosphatase 4A3 (PTP4A3) Promotes Vascular Endothelial Growth Factor Signaling and Enables Endothelial Cell Motility* , 2014, The Journal of Biological Chemistry.

[9]  Zhijian Zhao,et al.  Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[10]  D. Sabatini,et al.  Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids , 2010, Cell.

[11]  J. Blenis,et al.  Molecular mechanisms of mTOR-mediated translational control , 2009, Nature Reviews Molecular Cell Biology.

[12]  K. Inoki,et al.  Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. , 2003, Genes & development.

[13]  Q. Zeng,et al.  PRL-3 down-regulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. , 2007, Cancer research.

[14]  K. Mills,et al.  Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia , 2013, EMBO molecular medicine.

[15]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[16]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[17]  D. Sabatini,et al.  mTOR Signaling in Growth Control and Disease , 2012, Cell.

[18]  L. Cantley,et al.  Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation , 1985, Nature.

[19]  A. Teleman,et al.  Regulation of TORC1 in Response to Amino Acid Starvation via Lysosomal Recruitment of TSC2 , 2014, Cell.

[20]  J. Howell,et al.  A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets* , 2003, Journal of Biological Chemistry.

[21]  D. Alessi,et al.  Regulation of Akt/PKB Ser473 phosphorylation. , 2005, Molecular cell.

[22]  Paul Tempst,et al.  Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis , 2005, Cell.

[23]  Y. Li,et al.  Evaluation of PRL-3 expression, and its correlation with angiogenesis and invasion in hepatocellular carcinoma. , 2008, International journal of molecular medicine.

[24]  Michael A. Choti,et al.  A Phosphatase Associated with Metastasis of Colorectal Cancer , 2001, Science.

[25]  Xianglin Shi,et al.  Luteolin Inhibits Human Prostate Tumor Growth by Suppressing Vascular Endothelial Growth Factor Receptor 2-Mediated Angiogenesis , 2012, PloS one.

[26]  Q. Zeng,et al.  Generation of PRL-3- and PRL-1-Specific Monoclonal Antibodies as Potential Diagnostic Markers for Cancer Metastases , 2005, Clinical Cancer Research.

[27]  Robert T. Abraham,et al.  Phosphorylation of Mammalian Target of Rapamycin (mTOR) at Ser-2448 Is Mediated by p70S6 Kinase* , 2005, Journal of Biological Chemistry.

[28]  R. Cardiff,et al.  Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease , 1992, Molecular and cellular biology.

[29]  Christine C. Hudson,et al.  A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. , 2000, Cancer research.

[30]  K. Hess,et al.  Mechanisms of action of rapamycin in gliomas. , 2005, Neuro-oncology.

[31]  Q. Zeng,et al.  PRL‐3 phosphatase and cancer metastasis , 2010, Journal of cellular biochemistry.

[32]  D. Choi,et al.  ERK1/2 is involved in luteal cell autophagy regulation during corpus luteum regression via an mTOR-independent pathway. , 2014, Molecular human reproduction.

[33]  L. Cantley,et al.  Phosphatidylinositol metabolism and polyoma-mediated transformation. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[34]  X. Bai,et al.  Key factors in mTOR regulation , 2009, Cellular and Molecular Life Sciences.

[35]  Q. Zeng,et al.  Engineering the First Chimeric Antibody in Targeting Intracellular PRL-3 Oncoprotein for Cancer Therapy in Mice , 2012, Oncotarget.

[36]  D. Sabatini,et al.  Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1 , 2012, Cell.

[37]  C. Proud,et al.  Regulation of mammalian translation factors by nutrients. , 2002, European journal of biochemistry.

[38]  T. Krieg,et al.  Identification of activated matrix metalloproteinase‐2 (MMP‐2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography , 2002, The Journal of pathology.

[39]  L. Cantley,et al.  Spatial Control of the TSC Complex Integrates Insulin and Nutrient Regulation of mTORC1 at the Lysosome , 2014, Cell.

[40]  T. Roberts,et al.  A new class of mutations reveals a novel function for the original phosphatidylinositol 3-kinase binding site , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Avruch,et al.  Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action , 2002, Cell.

[42]  C. Shou,et al.  PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin β1-ERK1/2 and-MMP2 signaling , 2009, Molecular Cancer.

[43]  P. Finan,et al.  TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. , 2012, Molecular cell.

[44]  A. Gingras,et al.  4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. , 1998, Genes & development.

[45]  Tian Xu,et al.  Akt regulates growth by directly phosphorylating Tsc2 , 2002, Nature Cell Biology.

[46]  J. Blenis,et al.  The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. , 2011, Trends in biochemical sciences.

[47]  Yan Wang,et al.  SOX2 promotes the migration and invasion of laryngeal cancer cells by induction of MMP-2 via the PI3K/Akt/mTOR pathway. , 2014, Oncology reports.

[48]  S. Meloche,et al.  Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor , 2004, Journal of Biological Chemistry.

[49]  J. Thiery,et al.  A role of autophagy in PTP4A3-driven cancer progression , 2014, Autophagy.

[50]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[51]  David M Sabatini,et al.  Defining the role of mTOR in cancer. , 2007, Cancer cell.

[52]  R. Memmott,et al.  Akt-dependent and -independent mechanisms of mTOR regulation in cancer. , 2009, Cellular signalling.

[53]  B. Bauvois,et al.  New facets of matrix metalloproteinases MMP-2 and MMP-9 as cell surface transducers: outside-in signaling and relationship to tumor progression. , 2012, Biochimica et biophysica acta.

[54]  C. Betz,et al.  Where is mTOR and what is it doing there? , 2013, The Journal of cell biology.

[55]  David M. Sabatini,et al.  The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1 , 2008, Science.