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PMID: 22399812 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion.

Journal of cell science ·Vol. 125 ·No. Pt 5 ·2012-03-01 ·Pages 1259-73

Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R

Abstract

In cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition of mesenchymal properties, a process that can lead to epithelial-mesenchymal transition (EMT). TGF-β is a potent inducer of EMT, and increased TGF-β signaling in cancer cells is thought to drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) in cells undergoing EMT. TGF-β rapidly induces mTORC2 kinase activity in cells undergoing EMT, and controls epithelial cell progression through EMT. By regulating EMT-associated cytoskeletal changes and gene expression, mTORC2 is required for cell migration and invasion. Furthermore, inactivation of mTORC2 prevents cancer cell dissemination in vivo. Our results suggest that the mTORC2 pathway is an essential downstream branch of TGF-β signaling, and represents a responsive target to inhibit EMT and prevent cancer cell invasion and metastasis.

MeSH Terms
Animals Carcinoma, Squamous Cell/metabolism,pathology Carrier Proteins/genetics,metabolism Cell Line, Tumor Cell Movement Disease Progression Epithelial Cells/metabolism Epithelial-Mesenchymal Transition Matrix Metalloproteinase 9/biosynthesis Mice Neoplasm Invasiveness Neoplasms/metabolism,pathology Phosphorylation Proto-Oncogene Proteins c-akt/metabolism RNA Interference RNA, Messenger/biosynthesis RNA, Small Interfering Rapamycin-Insensitive Companion of mTOR Protein Signal Transduction/physiology Snail Family Transcription Factors TOR Serine-Threonine Kinases/metabolism Transcription Factors/genetics Transforming Growth Factor beta/metabolism rhoA GTP-Binding Protein/metabolism
Chemicals
Carrier Proteins RNA, Messenger RNA, Small Interfering Rapamycin-Insensitive Companion of mTOR Protein Snail Family Transcription Factors Transcription Factors Transforming Growth Factor beta rictor protein, mouse stress-activated protein kinase-interacting protein, mouse mTOR protein, mouse Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases Matrix Metalloproteinase 9 rhoA GTP-Binding Protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lamouille Samy
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA 94143-0512, USA.
Connolly Erin
Smyth James W
Akhurst Rosemary J
Derynck Rik
References (46)
46 references, click to expand
  1. Smad-dependent and Smad-independent pathways in TGF-beta family signalling.
    Nature. 2003 Oct 9;425(6958):577-84 PMID: 14534577
  2. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability.
    Dev Cell. 2006 Oct;11(4):583-9 PMID: 16962829
  3. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1.
    Dev Cell. 2006 Dec;11(6):859-71 PMID: 17141160
  4. Complex networks orchestrate epithelial-mesenchymal transitions.
    Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42 PMID: 16493418
  5. Non-Smad TGF-beta signals.
    J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84 PMID: 16105881
  6. Cooperative effects of Rho and mechanical stretch on stress fiber organization.
    Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15895-900 PMID: 16247009
  7. Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer.
    Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(8):314-23 PMID: 19838011
  8. Paxillin comes of age.
    J Cell Sci. 2008 Aug 1;121(Pt 15):2435-44 PMID: 18650496
  9. mTOR signaling at a glance.
    J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94 PMID: 19812304
  10. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
    Science. 2005 Feb 18;307(5712):1098-101 PMID: 15718470
  11. TGF-beta and epithelial-to-mesenchymal transitions.
    Oncogene. 2005 Aug 29;24(37):5764-74 PMID: 16123809
  12. EMT, the cytoskeleton, and cancer cell invasion.
    Cancer Metastasis Rev. 2009 Jun;28(1-2):15-33 PMID: 19169796
  13. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.
    Cancer Res. 2011 May 1;71(9):3246-56 PMID: 21430067
  14. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.
    Cell. 2006 Oct 6;127(1):125-37 PMID: 16962653
  15. Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival.
    Cancer Res. 2008 Mar 15;68(6):1618-24 PMID: 18339839
  16. Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis.
    Oncogene. 2011 Jun 30;30(26):2954-63 PMID: 21339740
  17. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.
    Science. 2005 Mar 11;307(5715):1603-9 PMID: 15761148
  18. Specificity and versatility in tgf-beta signaling through Smads.
    Annu Rev Cell Dev Biol. 2005;21:659-93 PMID: 16212511
  19. TGF-beta-mediated activation of RhoA signalling is required for efficient (V12)HaRas and (V600E)BRAF transformation.
    Oncogene. 2009 Feb 19;28(7):983-93 PMID: 19079344
  20. TGF-beta and cancer.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):29-40 PMID: 16289860
  21. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.
    Mol Biol Cell. 2001 Jan;12(1):27-36 PMID: 11160820
  22. Matrix metalloproteinases: regulators of the tumor microenvironment.
    Cell. 2010 Apr 2;141(1):52-67 PMID: 20371345
  23. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive.
    Nat Cell Biol. 2004 Nov;6(11):1122-8 PMID: 15467718
  24. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression.
    Cancer Sci. 2007 Oct;98(10):1512-20 PMID: 17645776
  25. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity.
    Genes Dev. 2006 Oct 15;20(20):2820-32 PMID: 17043309
  26. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
    Cell. 2003 Jun 13;113(6):685-700 PMID: 12809600
  27. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion.
    Cell Growth Differ. 1998 May;9(5):393-404 PMID: 9607560
  28. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors.
    J Cell Biol. 1994 Dec;127(6 Pt 2):2021-36 PMID: 7806579
  29. The LD4 motif of paxillin regulates cell spreading and motility through an interaction with paxillin kinase linker (PKL).
    J Cell Biol. 2001 Jul 9;154(1):161-76 PMID: 11448998
  30. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer.
    Nat Rev Cancer. 2006 Jul;6(7):506-20 PMID: 16794634
  31. TGF-beta-induced epithelial to mesenchymal transition.
    Cell Res. 2009 Feb;19(2):156-72 PMID: 19153598
  32. Loss of heterozygosity and mutational alterations of the p53 gene in skin tumours of interspecific hybrid mice.
    Oncogene. 1991 Dec;6(12):2363-9 PMID: 1766680
  33. Roles of TGFbeta in metastasis.
    Cell Res. 2009 Jan;19(1):89-102 PMID: 19050696
  34. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s.
    Curr Biol. 2006 Sep 19;16(18):1865-70 PMID: 16919458
  35. Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe.
    Am J Pathol. 2009 May;174(5):1588-93 PMID: 19342369
  36. Biomarkers for epithelial-mesenchymal transitions.
    J Clin Invest. 2009 Jun;119(6):1429-37 PMID: 19487819
  37. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway.
    J Cell Biol. 2007 Jul 30;178(3):437-51 PMID: 17646396
  38. Epithelial-mesenchymal transitions in development and disease.
    Cell. 2009 Nov 25;139(5):871-90 PMID: 19945376
  39. Genetic determinants of cancer metastasis.
    Nat Rev Genet. 2007 May;8(5):341-52 PMID: 17440531
  40. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor.
    J Cell Sci. 2005 Aug 1;118(Pt 15):3371-85 PMID: 16079281
  41. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition.
    Nat Cell Biol. 2004 Oct;6(10):931-40 PMID: 15448698
  42. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice.
    Cancer Cell. 2009 Feb 3;15(2):148-59 PMID: 19185849
  43. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.
    Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94 PMID: 15342917
  44. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition.
    J Cell Biol. 2005 Dec 19;171(6):1023-34 PMID: 16365168
  45. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells.
    Sci Signal. 2009 Oct 13;2(92):ra62 PMID: 19825827
  46. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.
    Curr Biol. 2004 Jul 27;14(14):1296-302 PMID: 15268862
Article Info
Journal
Journal of cell science
Abbr.
J Cell Sci
ISSN
1477-9137
DOI
10.1242/jcs.095299
Published
2012-03-01
Epub
2012-00-07
Pages
1259-73
Language
English
Region
England
NLM ID
0052457
PMCID
PMC3324583
Subset
IM
Grants
NCI NIH HHS · R01 CA116019 · United States
NHLBI NIH HHS · R01 HL078564 · United States
NCI NIH HHS · R01 CA136690 · United States
NCI NIH HHS · R01-CA116019 · United States
NHLBI NIH HHS · P01-HL60231 · United States
NHLBI NIH HHS · R01-HL078564 · United States
NCI NIH HHS · T32 CA108462 · United States
NHLBI NIH HHS · P01 HL060231 · United States
NIGMS NIH HHS · R01-GM60514 · United States
NCI NIH HHS · R01-CA136690 · United States
NIGMS NIH HHS · R01 GM060514 · United States
External Links
PubMed source DOI: 10.1242/jcs.095299 PMC Full Text View journal details
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