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Dual TORCs driven and B56 orchestrated signaling network guides eukaryotic cell migration

  • Kim, Lou W. (Department of Biological Sciences, Florida International University)
  • Received : 2017.02.23
  • Published : 2017.09.30

Abstract

Different types of eukaryotic cells may adopt seemingly distinct modes of directional cell migration. However, several core aspects are regarded common whether the movement is either ameoboidal or mesenchymal. The region of cells facing the attractive signal is often termed leading edge where lamellipodial structures dominates and the other end of the cell called rear end is often mediating cytoskeletal F-actin contraction involving Myosin-II. Dynamic remodeling of cell-to-matrix adhesion involving integrin is also evident in many types of migrating cells. All these three aspects of cell migration are significantly affected by signaling networks of TorC2, TorC1, and PP2A/B56. Here we review the current views of the mechanistic understanding of these regulatory signaling networks and how these networks affect eukaryotic cell migration.

Keywords

References

  1. Eichhorn PJA, Creyghton MP and Bernards R (2009) Protein phosphatase 2A regulatory subunits and cancer. Biochimica et Biophysica Acta 1795, 1-15
  2. Gutierrez-Caballero C, Cebollero LR and Pendas AM (2012) Shugoshins: from protectors of cohesion to versatile adaptors at the centromere. Trends Genet 28, 351-360 https://doi.org/10.1016/j.tig.2012.03.003
  3. Kurimchak A and Grana X (2015) PP2A: more than a reset switch to activate pRB proteins during the cell cycle and in response to signaling cues. Cell Cycle 14, 18-30 https://doi.org/10.4161/15384101.2014.985069
  4. Lillo C, Kataya AR, Heidari B et al (2014) Protein phosphatases PP2A, PP4 and PP6: mediators and regulators in development and responses to environmental cues. Plant Cell Environ 37, 2631-2648 https://doi.org/10.1111/pce.12364
  5. Mumby M (2007) PP2A: unveiling a reluctant tumor suppressor. Cell 130, 21-24 https://doi.org/10.1016/j.cell.2007.06.034
  6. Rahikainen M, Pascual J, Alegre S, Durian G and Kangasjarvi S (2016) PP2A Phosphatase as a Regulator of ROS Signaling in Plants. Antioxidants (Basel) 5, pii: E8
  7. Seshacharyulu P, Pandey P, Datta K and Batra SK (2013) Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett 335, 9-18 https://doi.org/10.1016/j.canlet.2013.02.036
  8. Stamos JL and Weis WI (2013) The ${\beta}$-catenin destruction complex. Cold Spring Harb Perspect Biol 5, a007898 https://doi.org/10.1101/cshperspect.a007898
  9. Janssens V and Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353(Pt 3), 417-439 https://doi.org/10.1042/bj3530417
  10. Murphy MB, Levi SK and Egelhoff TT (1999) Molecular characterization and immunolocalization of Dictyostelium discoideum protein phosphatase 2A. FEBS Lett 456, 7-12 https://doi.org/10.1016/S0014-5793(99)00835-2
  11. Lee NS, Veeranki S, Kim B and Kim L (2008) The function of PP2A/B56 in non-metazoan multicellular development. Differentiation 76, 1104-1110 https://doi.org/10.1111/j.1432-0436.2008.00301.x
  12. Rodriguez Pino M, Castillo B, Kim B and Kim LW (2015) PP2A/B56 and GSK3/Ras suppress PKB activity during Dictyostelium chemotaxis. Mol Biol Cell 26, 4347-4357 https://doi.org/10.1091/mbc.E14-06-1130
  13. Jiang L, Stanevich V, Satyshur KA et al (2013) Structural basis of protein phosphatase 2A stable latency. Nat Commun 4, 1699 https://doi.org/10.1038/ncomms2663
  14. Di Como CJ and Arndt KT (1996) Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev 10, 1904-1916 https://doi.org/10.1101/gad.10.15.1904
  15. Ogris E, Gibson DM and Pallas DC (1997) Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. Oncogene 15, 911-917 https://doi.org/10.1038/sj.onc.1201259
  16. Bryant JC, Westphal RS and Wadzinski BE (1999) Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. Biochem J 339, 241-246 https://doi.org/10.1042/bj3390241
  17. Hu X, Wu X, Xu J, Zhou J, Han X and Guo J (2009) Src kinase up-regulates the ERK cascade through inactivation of protein phosphatase 2A following cerebral ischemia. BMC Neurosci 10, 74 https://doi.org/10.1186/1471-2202-10-74
  18. Hong K, Lou L, Gupta S, Ribeiro-Neto F and Altschuler DL (2008) A novel Epac-Rap-PP2A signaling module controls cAMP-dependent Akt regulation. J Biol Chem 283, 23129-23138 https://doi.org/10.1074/jbc.M800478200
  19. Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P and Nairn AC (2007) Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci U S A 104, 2979-2984 https://doi.org/10.1073/pnas.0611532104
  20. Kirchhefer U, Heinick A, Konig S et al (2014) Protein phosphatase 2A is regulated by protein kinase $C{\alpha}(PKC{\alpha})$-dependent phosphorylation of its targeting subunit $B56{\alpha}$ at Ser41. J Biol Chem 289, 163-176 https://doi.org/10.1074/jbc.M113.507996
  21. Hertz EP, Kruse T, Davey NE et al (2016) A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase. Mol Cell 63, 686-695 https://doi.org/10.1016/j.molcel.2016.06.024
  22. Wang J, Wang Z, Yu T et al (2016) Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization. Protein Cell 7, 516-526 https://doi.org/10.1007/s13238-016-0283-4
  23. Xu Z, Cetin B, Anger M et al (2009) Structure and function of the PP2A-shugoshin interaction. Mol Cell 35, 426-441 https://doi.org/10.1016/j.molcel.2009.06.031
  24. Funamoto S, Meili R, Lee S, Parry L and Firtel RA (2002) Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109, 611-623 https://doi.org/10.1016/S0092-8674(02)00755-9
  25. Sasaki AT, Chun C, Takeda K and Firtel RA (2004) Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement. J Cell Biol 167, 505-518 https://doi.org/10.1083/jcb.200406177
  26. Cai H, Das S, Kamimura Y, Long Y, Parent CA and Devreotes PN (2010) Ras-mediated activation of the TORC2-PKB pathway is critical for chemotaxis. J Cell Biol 190, 233-245 https://doi.org/10.1083/jcb.201001129
  27. Kamimura Y and Devreotes PN (2010) Phosphoinositidedependent protein kinase (PDK) activity regulates phosphatidylinositol 3,4,5-trisphosphate-dependent and -independent protein kinase B activation and chemotaxis. J Biol Chem 285, 7938-7946 https://doi.org/10.1074/jbc.M109.089235
  28. Khanna A, Lotfi P, Chavan AJ et al (2016) The small GTPases Ras and Rap1 bind to and control TORC2 activity. Sci Rep 6, 25823 https://doi.org/10.1038/srep25823
  29. Artemenko Y, Lampert TJ and Devreotes PN (2014) Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes. Cell Mol Life Sci 71, 3711-3747 https://doi.org/10.1007/s00018-014-1638-8
  30. Devreotes P and Horwitz AR (2015) Signaling networks that regulate cell migration. Cold Spring Harb Perspect Biol 7, a005959 https://doi.org/10.1101/cshperspect.a005959
  31. Liu L, Das S, Losert W and Parent CA (2010) mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev Cell 19, 845-857 https://doi.org/10.1016/j.devcel.2010.11.004
  32. Diz-Munoz A, Thurley K, Chintamen S et al (2016) Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration. PLoS Biol 14, e1002474 https://doi.org/10.1371/journal.pbio.1002474
  33. Kuehn HS, Jung MY, Beaven MA, Metcalfe DD and Gilfillan AM (2011) Prostaglandin E2 activates and utilizes mTORC2 as a central signaling locus for the regulation of mast cell chemotaxis and mediator release. J Biol Chem 286, 391-402 https://doi.org/10.1074/jbc.M110.164772
  34. Insall RH, Borleis J and Devreotes PN (1996) The aimless RasGEF is required for processing of chemotactic signals through G-protein-coupled receptors in Dictyostelium. Curr Biol 6, 719-729 https://doi.org/10.1016/S0960-9822(09)00453-9
  35. Kae H, Kortholt A, Rehmann H et al (2007) Cyclic AMP signalling in Dictyostelium: G-proteins activate separate Ras pathways using specific RasGEFs. EMBO Rep 8, 477-482 https://doi.org/10.1038/sj.embor.7400936
  36. Kamimura Y, Xiong Y, Iglesias PA, Hoeller O, Bolourani P and Devreotes PN (2008) PIP3-independent activation of TorC2 and PKB at the cell's leading edge mediates chemotaxis. Curr Biol 18, 1034-1043 https://doi.org/10.1016/j.cub.2008.06.068
  37. Lee S, Comer FI, Sasaki A et al (2005) TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol Biol Cell 16, 4572-4583 https://doi.org/10.1091/mbc.E05-04-0342
  38. Liu Y, Lacal J, Veltman DM et al (2016) A $G{\alpha}$-Stimulated RapGEF Is a Receptor-Proximal Regulator of Dictyostelium Chemotaxis. Dev Cell 37, 458-472 https://doi.org/10.1016/j.devcel.2016.05.001
  39. Chen MY, Long Y and Devreotes PN (1997) A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the 12 transmembrane domain adenylyl cyclase in Dictyostelium. Genes Dev 11, 3218-3231 https://doi.org/10.1101/gad.11.23.3218
  40. He Y, Li D, Cook SL et al (2013) Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol Biol Cell 24, 3369-3380 https://doi.org/10.1091/mbc.E13-07-0405
  41. Agarwal NK, Chen CH, Cho H, Boulbes DR, Spooner E and Sarbassov DD (2013) Rictor regulates cell migration by suppressing RhoGDI2. Oncogene 32, 2521-2526 https://doi.org/10.1038/onc.2012.287
  42. Zhang F, Zhang X, Li M et al (2010) mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis. Cancer Res 70, 9360-9370 https://doi.org/10.1158/0008-5472.CAN-10-0207
  43. Xu Y, Lai E, Liu J et al (2013) IKK interacts with rictor and regulates mTORC2. Cell Signal 25, 2239-2245 https://doi.org/10.1016/j.cellsig.2013.07.008
  44. Julien LA, Carriere A, Moreau J and Roux PP (2010) mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 30, 908-921 https://doi.org/10.1128/MCB.00601-09
  45. Chen CH, Shaikenov T, Peterson TR et al (2011) ER stress inhibits mTORC2 and Akt signaling through GSK-3betamediated phosphorylation of rictor. Sci Signal 4, ra10
  46. Humphrey SJ, Yang G, Yang P et al (2013) Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 17, 1009-1020 https://doi.org/10.1016/j.cmet.2013.04.010
  47. Liu P, Gan W, Inuzuka H et al (2013) Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 15, 1340-1350 https://doi.org/10.1038/ncb2860
  48. Meili R, Ellsworth C, Lee S, Reddy TB, Ma H and Firtel RA (1999) Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J 18, 2092-2105 https://doi.org/10.1093/emboj/18.8.2092
  49. Liao XH, Buggey J, Lee YK and Kimmel AR (2013) Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium. Mol Biol Cell 24, 2146-2155 https://doi.org/10.1091/mbc.E13-03-0130
  50. Yagi M, Kantarci A, Iwata T et al (2009) PDK1 regulates chemotaxis in human neutrophils. J Dent Res 88, 1119-1124 https://doi.org/10.1177/0022034509349402
  51. Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP and Tissenbaum HA (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136, 939-951 https://doi.org/10.1016/j.cell.2009.01.025
  52. Letourneux C, Rocher G and Porteu F (2006) B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J 25, 727-738 https://doi.org/10.1038/sj.emboj.7600980
  53. Rocher G, Letourneux C, Lenormand P and Porteu F (2007) Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity. J Biol Chem 282, 5468-5477 https://doi.org/10.1074/jbc.M609712200
  54. Rodgers JT, Vogel RO and Puigserver P (2011) Clk2 and $B56{\beta}$ mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt. Mol Cell 41, 471-479 https://doi.org/10.1016/j.molcel.2011.02.007
  55. Charest PG, Shen Z, Lakoduk A, Sasaki AT, Briggs SP and Firtel RA (2010) A Ras signaling complex controls the RasC-TORC2 pathway and directed cell migration. Dev Cell 18, 737-749 https://doi.org/10.1016/j.devcel.2010.03.017
  56. Swaney KF, Huang CH and Devreotes PN (2010) Eukaryotic chemotaxis: a network of signaling pathways controls motility, directional sensing, and polarity. Annu Rev Biophys 39, 265-289 https://doi.org/10.1146/annurev.biophys.093008.131228
  57. Liu L, Chen L, Chung J and Huang S (2008) Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene 27, 4998-5010 https://doi.org/10.1038/onc.2008.137
  58. Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6, 1122-1128 https://doi.org/10.1038/ncb1183
  59. Le OT, Cho OY, Tran MH et al (2015) Phosphorylation of phosphatidylinositol 4-phosphate 5-kinase ${\gamma}$ by Akt regulates its interaction with talin and focal adhesion dynamics. Biochimica et Biophysica Acta 1853, 2432-2443 https://doi.org/10.1016/j.bbamcr.2015.07.001
  60. Sen B, Xie Z, Case N et al (2014) mTORC2 Regulates Mechanically Induced Cytoskeletal Reorganization and Lineage Selection in Marrow-Derived Mesenchymal Stem Cells. J Bone Miner Res 29, 78-89 https://doi.org/10.1002/jbmr.2031
  61. Ravi A, Kaushik S, Ravichandran A, Pan CQ and Low BC (2015) Epidermal Growth Factor Activates the Rho GTPase-activating Protein (GAP) Deleted in Liver Cancer 1 via Focal Adhesion Kinase and Protein Phosphatase 2A. J Biol Chem 290, 4149-4162 https://doi.org/10.1074/jbc.M114.616839
  62. Lamouille S and Derynck R (2011) Emergence of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin axis in transforming growth factor-${\beta}$-induced epithelial-mesenchymal transition. Cells Tissues Organs 193, 8-22 https://doi.org/10.1159/000320172
  63. Sato T, Ishii J, Ota Y, Sasaki E, Shibagaki Y and Hattori S (2016) Mammalian target of rapamycin (mTOR) complex 2 regulates filamin A-dependent focal adhesion dynamics and cell migration. Genes Cells 21, 579-593 https://doi.org/10.1111/gtc.12366
  64. Tsujioka M, Yumura S, Inouye K, Patel H, Ueda M and Yonemura S (2012) Talin couples the actomyosin cortex to the plasma membrane during rear retraction and cytokinesis. Proc Natl Acad Sci U S A 109, 12992-12997 https://doi.org/10.1073/pnas.1208296109
  65. Yan L, Mieulet V, Burgess D et al (2010) PP2AT613 Is an Inhibitor of MAP4K3 in Nutrient Signaling to mTOR. Molecular Cell 37, 633-642 https://doi.org/10.1016/j.molcel.2010.01.031
  66. Tomar A and Schlaepfer DD (2009) Focal adhesion kinase: switching between GAPs and GEFs in the regulation of cell motility. Curr Opin Cell Biol 21, 676-683 https://doi.org/10.1016/j.ceb.2009.05.006
  67. Liu L, Luo Y, Chen L et al (2010) Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J Biol Chem 285, 38362-38373 https://doi.org/10.1074/jbc.M110.141168
  68. Berven LA, Willard FS and Crouch MF (2004) Role of the p70(S6K) pathway in regulating the actin cytoskeleton and cell migration. Exp Cell Res 296, 183-195 https://doi.org/10.1016/j.yexcr.2003.12.032
  69. Poon M, Marx SO, Gallo R, Badimon JJ, Taubman MB and Marks AR (1996) Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 98, 2277-2283 https://doi.org/10.1172/JCI119038
  70. Sakakibara K, Liu B, Hollenbeck S and Kent KC (2005) Rapamycin inhibits fibronectin-induced migration of the human arterial smooth muscle line (E47) through the mammalian target of rapamycin. Am J Physiol Heart Circ Physiol 288, H2861-H2868 https://doi.org/10.1152/ajpheart.00561.2004
  71. Attoub S, Noe V, Pirola L et al (2000) Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways. FASEB J 14, 2329-2338 https://doi.org/10.1096/fj.00-0162
  72. Wong AS, Roskelley CD, Pelech S, Miller D, Leung PC and Auersperg N (2004) Progressive changes in Metdependent signaling in a human ovarian surface epithelial model of malignant transformation. Exp Cell Res 299, 248-256 https://doi.org/10.1016/j.yexcr.2004.06.002
  73. Wan X, Mendoza A, Khanna C and Helman LJ (2005) Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res 65, 2406-2411 https://doi.org/10.1158/0008-5472.CAN-04-3135
  74. Liu L, Li F, Cardelli JA, Martin KA, Blenis J and Huang S (2006) Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 25, 7029-7040 https://doi.org/10.1038/sj.onc.1209691
  75. Zhou HY and Wong AS (2006) Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells. Endocrinology 147, 2557-2566 https://doi.org/10.1210/en.2005-1404
  76. Maegawa K, Takii R, Ushimaru T and Kozaki A (2015) Evolutionary conservation of TORC1 components, TOR, Raptor, and LST8, between rice and yeast. Mol Genet Genomics 290, 2019-2030 https://doi.org/10.1007/s00438-015-1056-0
  77. Otterhag L, Gustavsson N, Alsterfjord M et al (2006) Arabidopsis PDK1: identification of sites important for activity and downstream phosphorylation of S6 kinase. Biochimie 88, 11-21 https://doi.org/10.1016/j.biochi.2005.07.005
  78. Dobrenel T, Marchive C, Sormani R et al (2011) Regulation of plant growth and metabolism by the TOR kinase. Biochem Soc Trans 39, 477-481 https://doi.org/10.1042/BST0390477
  79. Ahn CS, Han JA, Lee HS, Lee S and Pai HS (2011) The PP2A regulatory subunit Tap46, a component of the TOR signaling pathway, modulates growth and metabolism in plants. Plant Cell 23, 185-209 https://doi.org/10.1105/tpc.110.074005
  80. Sommer LM, Cho H, Choudhary M and Seeling JM (2015) Evolutionary Analysis of the B56 Gene Family of PP2A Regulatory Subunits. Int J Mol Sci 16, 10134-10157 https://doi.org/10.3390/ijms160510134
  81. Wen F, Wang J and Xing D (2012) A protein phosphatase 2A catalytic subunit modulates blue light-induced chloroplast avoidance movements through regulating actin cytoskeleton in Arabidopsis. Plant Cell Physiol 53, 1366-1379 https://doi.org/10.1093/pcp/pcs081
  82. Konert G, Rahikainen M, Trotta A et al (2015) Subunits $B^{\prime}{\gamma}$ and $B^{\prime}{\zeta}$ of protein phosphatase 2A regulate photooxidative stress responses and growth in Arabidopsis thaliana. Plant Cell Environ 38, 2641-2651 https://doi.org/10.1111/pce.12575
  83. Jin L, Ham JH, Hage R et al (2016) Direct and Indirect Targeting of PP2A by Conserved Bacterial Type-III Effector Proteins. PLoS Pathog 12, e1005609 https://doi.org/10.1371/journal.ppat.1005609
  84. Durian G, Rahikainen M, Alegre S, Brosche M and Kangasjarvi S (2016) Protein Phosphatase 2A in the Regulatory Network Underlying Biotic Stress Resistance in Plants. Front Plant Sci 7, 812
  85. Vernoud V, Horton AC, Yang Z and Nielsen E (2003) Analysis of the small GTPase gene superfamily of Arabidopsis. Plant Physiol 131, 1191-1208 https://doi.org/10.1104/pp.013052
  86. Hussey PJ and Tijs Ketelaar T (2006) Control of the Actin Cytoskeleton in Plant Cell Growth. Annu Rev Plant Biol 57, 109-125 https://doi.org/10.1146/annurev.arplant.57.032905.105206