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Protein phosphatase 2A plays an important role in migration of bone marrow stroma cells

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Abstract

Administration of bone marrow stroma cells (BMSCs) has the potential to ameliorate degenerative disorders and to repair injured sites. The homing of transplanted BMSCs to damaged tissues is a critical property of engraftment. Therefore, it is important to understand signal molecules controlling migration of BMSCs. Here, we demonstrate that serine-threonine protein phosphatase 2A (PP2A) is responsive to migration of BMSCs. Pharmacological Inhibition of PP2A, using okadaic acid (OA), leads to attenuated cell migration in rat primary BMSCs both in the absence or presence of stromal cell-derived factor-1 (SDF-1). Consistent with the above findings, knockdown of the main catalytic subunit PP2Acα using small interfering RNA also attenuates chemotaxis of BMSCs. On the other hand, cell viability of BMSCs remains unchanged with OA treatment or knockdown of PP2Acα subunit. Moreover, we observed an upregulation of PP2A-B55β in transcription level after SDF-1 treatment, indicating their potential role as the functioning regulatory subunit of PP2A phosphatase in BMSCs migration model. Collectively, these data provide first insight into the modulation of BMSCs migration by PP2A phosphatase activity and lay a foundation for exploring PP2A signaling as a modulating target for BMSCs transplantation.

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References

  1. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705

    Article  PubMed  CAS  Google Scholar 

  2. Yoon YS, Lee N, Scadova H (2005) Myocardial regeneration with bone-marrow-derived stem cells. Biol Cell 97:253–263

    Article  PubMed  CAS  Google Scholar 

  3. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313

    Article  PubMed  CAS  Google Scholar 

  4. Battiwalla M, Hematti P (2009) Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy 11:503–515

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Tsuboi K, Itabashi Y, Ikeda Y, Ogawa S, Okano H, Hotta T, Ando K, Fukuda K (2004) Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104:3581–3587

    Article  PubMed  CAS  Google Scholar 

  6. Ng F, Boucher S, Koh S, Sastry KS, Chase L, Lakshmipathy U, Choong C, Yang Z, Vemuri MC, Rao MS, Tanavde V (2008) PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood 112:295–307

    Article  PubMed  CAS  Google Scholar 

  7. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H (2008) Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180:2581–2587

    Article  PubMed  CAS  Google Scholar 

  8. Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S (2005) Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 105:3793–3801

    Article  PubMed  CAS  Google Scholar 

  9. Dar A, Goichberg P, Shinder V, Kalinkovich A, Kollet O, Netzer N, Margalit R, Zsak M, Nagler A, Hardan I, Resnick I, Rot A, Lapidot T (2005) Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat Immunol 6:1038–1046

    Article  PubMed  CAS  Google Scholar 

  10. Lapidot T, Kollet O (2002) The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2 m(null) mice. Leukemia 16:1992–2003

    Article  PubMed  CAS  Google Scholar 

  11. Ma Q, Jones D, Springer TA (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10:463–471

    Article  PubMed  CAS  Google Scholar 

  12. Dutt P, Wang JF, Groopman JE (1998) Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J Immunol 161:3652–3658

    PubMed  CAS  Google Scholar 

  13. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599

    Article  PubMed  CAS  Google Scholar 

  14. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci USA 95:9448–9453

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PM, Raymond E (2014) Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. Am J Transl Res 6:340–352

    PubMed  PubMed Central  Google Scholar 

  16. Qiu M, Liu L, Chen L, Tan G, Liang Z, Wang K, Liu J, Chen H (2014) microRNA-183 plays as oncogenes by increasing cell proliferation, migration and invasion via targeting protein phosphatase 2A in renal cancer cells. Biochem Biophys Res Commun 452:163–169

    Article  PubMed  CAS  Google Scholar 

  17. Kawahara E, Maenaka S, Shimada E, Nishimura Y, Sakurai H (2013) Dynamic regulation of extracellular signal-regulated kinase (ERK) by protein phosphatase 2A regulatory subunit B56gamma1 in nuclei induces cell migration. PLoS One 8:e63729

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Basu S, Ray NT, Atkinson SJ, Broxmeyer HE (2007) Protein phosphatase 2A plays an important role in stromal cell-derived factor-1/CXC chemokine ligand 12-mediated migration and adhesion of CD34+ cells. J Immunol 179:3075–3085

    Article  PubMed  CAS  Google Scholar 

  19. Janssens V, Longin S, Goris J (2008) PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci 33:113–121

    Article  PubMed  CAS  Google Scholar 

  20. Chen W, Gu P, Jiang X, Ruan HB, Li C, Gao X (2011) Protein phosphatase 2A catalytic subunit alpha (PP2Acalpha) maintains survival of committed erythroid cells in fetal liver erythropoiesis through the STAT5 pathway. Am J Pathol 178:2333–2343

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353:417–439

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Sontag E (2001) Protein phosphatase 2A: the trojan horse of cellular signaling. Cell Signal 13:7–16

    Article  PubMed  CAS  Google Scholar 

  23. Arino J, Woon CW, Brautigan DL, Miller TB Jr, Johnson GL (1988) Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes. Proc Natl Acad Sci USA 85:4252–4256

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Khew-Goodall Y, Hemmings BA (1988) Tissue-specific expression of mRNAs encoding alpha- and beta-catalytic subunits of protein phosphatase 2A. FEBS Lett 238:265–268

    Article  PubMed  CAS  Google Scholar 

  25. Khew-Goodall Y, Mayer RE, Maurer F, Stone SR, Hemmings BA (1991) Structure and transcriptional regulation of protein phosphatase 2A catalytic subunit genes. Biochemistry 30:89–97

    Article  PubMed  CAS  Google Scholar 

  26. Shi Y (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139:468–484

    Article  PubMed  CAS  Google Scholar 

  27. He J, Teng X, Yu Y, Huang H, Ye W, Ding Y, Shen Z (2013) Injection of Sca-1+/CD45+/CD31+ mouse bone mesenchymal stromal-like cells improves cardiac function in a mouse myocardial infarct model. Differentiation 86:57–64

    Article  PubMed  CAS  Google Scholar 

  28. Chen W, Li C, Jiang X, Ruan H, Qi X, Liu L, Zhao Q, Gao X (2010) Overexpressing dominant negative MyD88 induces cardiac dysfunction in transgenic mice. Chin Sci Bull 55:3569–3575

    Article  CAS  Google Scholar 

  29. Wu J, Dong Y, Teng X, Cheng M, Shen Z, Chen W (2015) Follistatin-like 1 attenuates differentiation and survival of erythroid cells through Smad2/3 signaling. Biochem Biophys Res Commun 466:711–716

    Article  PubMed  CAS  Google Scholar 

  30. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8:315–317

    Article  PubMed  CAS  Google Scholar 

  31. Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem J 256:283–290

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Millward TA, Zolnierowicz S, Hemmings BA (1999) Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24:186–191

    Article  PubMed  CAS  Google Scholar 

  33. Namboodiripad AN, Jennings ML (1996) Permeability characteristics of erythrocyte membrane to okadaic acid and calyculin A. Am J Physiol 270:C449–C456

    PubMed  CAS  Google Scholar 

  34. Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J (2004) Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 18:29–40

    Article  PubMed  CAS  Google Scholar 

  35. Xia W, Xie C, Jiang M, Hou M (2015) Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor. Mol Cell Biochem 404:11–24

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Kong M, Bui TV, Ditsworth D, Gruber JJ, Goncharov D, Krymskaya VP, Lindsten T, Thompson CB (2007) The PP2A-associated protein alpha4 plays a critical role in the regulation of cell spreading and migration. J Biol Chem 282:29712–29720

    Article  PubMed  CAS  Google Scholar 

  37. Liu J, Prickett TD, Elliott E, Meroni G, Brautigan DL (2001) Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Proc Natl Acad Sci USA 98:6650–6655

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Schweiger S, Schneider R (2003) The MID1/PP2A complex: a key to the pathogenesis of Opitz BBB/G syndrome. BioEssays 25:356–366

    Article  PubMed  CAS  Google Scholar 

  39. Xu L, Deng X (2006) Suppression of cancer cell migration and invasion by protein phosphatase 2A through dephosphorylation of mu- and m-calpains. J Biol Chem 281:35567

    Article  PubMed  CAS  Google Scholar 

  40. Ito A, Kataoka TR, Watanabe M, Nishiyama K, Mazaki Y, Sabe H, Kitamura Y, Nojima H (2000) A truncated isoform of the PP2A B56 subunit promotes cell motility through paxillin phosphorylation. EMBO J 19:562–571

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Latta EJ, Golding JP (2012) Regulation of PP2A activity by Mid1 controls cranial neural crest speed and gangliogenesis. Mech Dev 128:560–576

    Article  PubMed  CAS  Google Scholar 

  42. Dagda RK, Merrill RA, Cribbs JT, Chen Y, Hell JW, Usachev YM, Strack S (2008) The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem 283:36241–36248

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Cheng WT, Guo ZX, Lin CA, Lin MY, Tung LC, Fang K (2009) Oxidative stress promotes autophagic cell death in human neuroblastoma cells with ectopic transfer of mitochondrial PPP2R2B (Bbeta2). BMC Cell Biol 10:91

    Article  PubMed  PubMed Central  Google Scholar 

  44. Crispin JC, Apostolidis SA, Finnell MI, Tsokos GC (2011) Induction of PP2A Bbeta, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus. Proc Natl Acad Sci USA 108:12443–12448

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Jiangsu Province’s Key Discipline / Laboratory of Medicine (XK201118), Chinese National Natural Science Foundation Projects (31401239), and Natural Science Fund for Colleges and Universities in Jiangsu Province (14KJB180021).

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    Authors and Affiliations

    1. Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, 215006, Jiangsu, China

      Weiqian Chen, Shizhen Wang, Jun Xia & Zhenya Shen

    2. Jiangsu Province Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agriculture University, Nanjing, 210095, Jiangsu, China

      Zan Huang

    3. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, Jiangsu, China

      Xin Tu

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    1. Weiqian Chen
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    Correspondence to Zhenya Shen.

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    Weiqian Chen, Shizhen Wang and Jun Xia have contributed equally to this article

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    Chen, W., Wang, S., Xia, J. et al. Protein phosphatase 2A plays an important role in migration of bone marrow stroma cells. Mol Cell Biochem 412, 173–180 (2016). https://doi.org/10.1007/s11010-015-2624-7

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