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Cited by 151Protein Kinase Regulation and GTPase SignalingCellular Mechanics and InteractionsIon Channels and Receptors

Ca 2+ influx is an essential component of the positive-feedback loop that maintains leading-edge structure and activity in macrophages

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Evans, John H., Falke, Joseph J.·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0707719104PMC PMC2042181
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Abstract

In migrating eukaryotic cells, phosphatidylinositol 3-kinase (PI3K), filamentous actin (F-actin), and monomeric Rho GTPases are key components of a complex positive-feedback system that maintains and amplifies a phosphatidylinositol-3,4,5-trisphosphate signal at the leading edge of the cell. This lipid signal is required for cell polarization and movement. In leukocytes and Dictyostelium , activation or inhibition of any one of these components leads to the activation or inhibition, respectively, of the others via undefined feedback interactions. The role of Ca 2+ signals in migrating leukocytes is controversial, and there has been no indication that Ca 2+ participates in positive feedback. Here, we demonstrate that an extracellular Ca 2+ influx is required for positive feedback at the leading edge of spontaneously polarized macrophages. Inhibition of extracellular Ca 2+ influx leads to loss of leading-edge PI3K activity, disassembly of F-actin, cessation of ruffling, and decay of chemoattractant signals. Conversely, increasing cytosolic Ca 2+ enhances membrane ruffling, PI3K activity, and F-actin accumulation. Overall, these findings demonstrate that an extracellular Ca 2+ influx is an essential component, together with PI3K and F-actin, of the positive-feedback cycle that maintains leading-edge structure and ruffling activity and that supports the chemoattractant response. Strikingly, the Ca 2+ -sensitive enzyme protein kinase Cα (PKCα) is enriched at the leading edge, and its enrichment is sensitive to blockade of Ca 2+ influx, to inhibition of PI3K activity, and to F-actin depolymerization. These findings support the working hypothesis that a local, leading-edge Ca 2+ signal recruits PKCα as a central player in the positive-feedback loop.

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  • Local changes in intracellular calcium play a critical role in regulating cell migration and chemotaxis in diverse cell types.

    “Local changes in intracellular calcium play a critical role in regulating cell migration and chemotaxis in diverse cell types48–50.”

    From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [49]

    The Discussion reports that calcium influx is essential for leading-edge activity in RAW macrophages and cites earlier evidence linking calcium entry to directed migration in neutrophils. It also says further studies are needed to determine whether this applies to other migrating cells. The claim's extension to diverse cell types is therefore not established by this paper. (LLM, conf=0.88)

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  1. [1]Becker EL, Showell HJ. Z Immunitatsforsch Exp Klin Immunol. 1972;143:466–476. [PubMed] [Google Scholar]
  2. [2]Gallin JI, Rosenthal AS. J Cell Biol. 1974;62:594–609. doi: 10.1083/jcb.62.3.594. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  3. [3]Wilkinson PC. Exp Cell Res. 1975;93:420–426. doi: 10.1016/0014-4827(75)90468-1. [DOI] [PubMed] [Google Scholar] · DOI
  4. [4]Estensen RD, Reusch ME, Epstein ML, Hill HR. Infect Immun. 1976;13:146–151. doi: 10.1128/iai.13.1.146-151.1976. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  5. [5]Boucek MM, Snyderman R. Science. 1976;193:905–907. doi: 10.1126/science.948752. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Zigmond SH. J Cell Biol. 1977;75:606–616. doi: 10.1083/jcb.75.2.606. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  7. [7]Marasco WA, Becker EL, Oliver JM. Am J Pathol. 1980;98:749–768. [PMC free article] [PubMed] [Google Scholar]
  8. [8]Mandeville JT, Ghosh RN, Maxfield FR. Biophys J. 1995;68:1207–1217. doi: 10.1016/S0006-3495(95)80336-X. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  9. [9]Sawyer DW, Sullivan JA, Mandell GL. Science. 1985;230:663–666. doi: 10.1126/science.4048951. [DOI] [PubMed] [Google Scholar] · DOI
  10. [10]Marks PW, Maxfield FR. J Cell Biol. 1990;110:43–52. doi: 10.1083/jcb.110.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. [11]Ching TT, Hsu AL, Johnson AJ, Chen CS. J Biol Chem. 2001;276:14814–14820. doi: 10.1074/jbc.M009851200. [DOI] [PubMed] [Google Scholar] · DOI
  12. [12]Hsu AL, Ching TT, Sen G, Wang DS, Bondada S, Authi KS, Chen CS. J Biol Chem. 2000;275:16242–16250. doi: 10.1074/jbc.M002077200. [DOI] [PubMed] [Google Scholar] · DOI
  13. [13]Tian W, Laffafian I, Dewitt S, Hallett MB. EMBO Rep. 2003;4:982–988. doi: 10.1038/sj.embor.embor947. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [14]Parent CA. Curr Opin Cell Biol. 2004;16:4–13. doi: 10.1016/j.ceb.2003.11.008. [DOI] [PubMed] [Google Scholar] · DOI
  15. [15]Franca-Koh J, Kamimura Y, Devreotes P. Curr Opin Genet Dev. 2006;16:333–338. doi: 10.1016/j.gde.2006.06.001. [DOI] [PubMed] [Google Scholar] · DOI
  16. [16]Charest PG, Firtel RA. Curr Opin Genet Dev. 2006;16:339–347. doi: 10.1016/j.gde.2006.06.016. [DOI] [PubMed] [Google Scholar] · DOI
  17. [17]Weiner OD, Neilsen PO, Prestwich GD, Kirschner MW, Cantley LC, Bourne HR. Nat Cell Biol. 2002;4:509–513. doi: 10.1038/ncb811. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. [18]Wang F, Herzmark P, Weiner OD, Srinivasan S, Servant G, Bourne HR. Nat Cell Biol. 2002;4:513–518. doi: 10.1038/ncb810. [DOI] [PubMed] [Google Scholar] · DOI
  19. [19]Xu J, Wang F, Van Keymeulen A, Herzmark P, Straight A, Kelly K, Takuwa Y, Sugimoto N, Mitchison T, Bourne HR. Cell. 2003;114:201–214. doi: 10.1016/s0092-8674(03)00555-5. [DOI] [PubMed] [Google Scholar] · DOI
  20. [20]Funamoto S, Milan K, Meili R, Firtel RA. J Cell Biol. 2001;153:795–810. doi: 10.1083/jcb.153.4.795. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. [21]Weiner OD, Servant G, Welch MD, Mitchison TJ, Sedat JW, Bourne HR. Nat Cell Biol. 1999;1:75–81. doi: 10.1038/10042. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. [22]Srinivasan S, Wang F, Glavas S, Ott A, Hofmann F, Aktories K, Kalman D, Bourne HR. J Cell Biol. 2003;160:375–385. doi: 10.1083/jcb.200208179. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  23. [23]Park KC, Rivero F, Meili R, Lee S, Apone F, Firtel RA. EMBO J. 2004;23:4177–4189. doi: 10.1038/sj.emboj.7600368. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. [24]Servant G, Weiner OD, Herzmark P, Balla T, Sedat JW, Bourne HR. Science. 2000;287:1037–1040. doi: 10.1126/science.287.5455.1037. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [25]Funamoto S, Meili R, Lee S, Parry L, Firtel RA. Cell. 2002;109:611–623. doi: 10.1016/s0092-8674(02)00755-9. [DOI] [PubMed] [Google Scholar] · DOI
  26. [26]Watanabe N, Mitchison TJ. Science. 2002;295:1083–1086. doi: 10.1126/science.1067470. [DOI] [PubMed] [Google Scholar] · DOI
  27. [27]Arrieumerlou C, Meyer T. Dev Cell. 2005;8:215–227. doi: 10.1016/j.devcel.2004.12.007. [DOI] [PubMed] [Google Scholar] · DOI
  28. [28]Qiu ZH, Gijon MA, de Carvalho MS, Spencer DM, Leslie CC. J Biol Chem. 1998;273:8203–8211. doi: 10.1074/jbc.273.14.8203. [DOI] [PubMed] [Google Scholar] · DOI
  29. [29]Dubyak GR, el-Moatassim C. Am J Physiol. 1993;265:C577–606. doi: 10.1152/ajpcell.1993.265.3.C577. [DOI] [PubMed] [Google Scholar] · DOI
  30. [30]Evans JH, Murray D, Leslie CC, Falke JJ. Mol Biol Cell. 2006;17:56–66. doi: 10.1091/mbc.E05-06-0499. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  31. [31]Corbin JA, Evans JH, Landgraf KE, Falke JJ. Biochemistry. 2007;46:4322–4336. doi: 10.1021/bi062140c. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. [32]Raghunath A, Ling M, Larsson C. Biochem J. 2003;370:901–912. doi: 10.1042/BJ20021420. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  33. [33]Oancea E, Meyer T. Cell. 1998;95:307–318. doi: 10.1016/s0092-8674(00)81763-8. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  34. [34]Medkova M, Cho W. J Biol Chem. 1999;274:19852–19861. doi: 10.1074/jbc.274.28.19852. [DOI] [PubMed] [Google Scholar] · DOI
  35. [35]Lenz JC, Reusch HP, Albrecht N, Schultz G, Schaefer M. J Cell Biol. 2002;159:291–302. doi: 10.1083/jcb.200203048. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [36]Reither G, Schaefer M, Lipp P. J Cell Biol. 2006;174:521–533. doi: 10.1083/jcb.200604033. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. [37]Neher E, Augustine GJ. J Physiol. 1992;450:273–301. doi: 10.1113/jphysiol.1992.sp019127. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  38. [38]Sala F, Hernandez-Cruz A. Biophys J. 1990;57:313–324. doi: 10.1016/S0006-3495(90)82533-9. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  39. [39]Kwon Y, Hofmann T, Montell C. Mol Cell. 2007;25:491–503. doi: 10.1016/j.molcel.2007.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. [40]Ramsey IS, Delling M, Clapham DE. Annu Rev Physiol. 2006;68:619–647. doi: 10.1146/annurev.physiol.68.040204.100431. [DOI] [PubMed] [Google Scholar] · DOI
  41. [41]Wang GX, Poo MM. Nature. 2005;434:898–904. doi: 10.1038/nature03478. [DOI] [PubMed] [Google Scholar] · DOI
  42. [42]Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB. Nature. 2005;434:894–898. doi: 10.1038/nature03477. [DOI] [PubMed] [Google Scholar] · DOI
  43. [43]Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N, Zinkernagel A, Nizet V, Insel PA, Junger WG. Science. 2006;314:1792–1795. doi: 10.1126/science.1132559. [DOI] [PubMed] [Google Scholar] · DOI
  44. [44]Lockyer PJ, Kupzig S, Cullen PJ. Curr Biol. 2001;11:981–986. doi: 10.1016/s0960-9822(01)00261-5. [DOI] [PubMed] [Google Scholar] · DOI
  45. [45]Zhang J, Guo J, Dzhagalov I, He YW. Nat Immunol. 2005;6:911–919. doi: 10.1038/ni1232. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  46. [46]Suire S, Hawkins P, Stephens L. Curr Biol. 2002;12:1068–1075. doi: 10.1016/s0960-9822(02)00933-8. [DOI] [PubMed] [Google Scholar] · DOI
  47. [47]Hartwig JH, Thelen M, Rosen A, Janmey PA, Nairn AC, Aderem A. Nature. 1992;356:618–622. doi: 10.1038/356618a0. [DOI] [PubMed] [Google Scholar] · DOI
  48. [48]Myat MM, Anderson S, Allen LA, Aderem A. Curr Biol. 1997;7:611–614. doi: 10.1016/s0960-9822(06)00262-4. [DOI] [PubMed] [Google Scholar] · DOI
  49. [49]Peters-Golden M. Am J Respir Cell Mol Biol. 2004;31:3–7. doi: 10.1165/rcmb.f279. [DOI] [PubMed] [Google Scholar] · DOI
  50. [50]Barnes PJ. COPD. 2004;1:59–70. doi: 10.1081/COPD-120028701. [DOI] [PubMed] [Google Scholar] · DOI
  51. [51]Kinne RW, Brauer R, Stuhlmuller B, Palombo-Kinne E, Burmester GR. Arthritis Res. 2000;2:189–202. doi: 10.1186/ar86. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Evans, J. H., & Falke, J. J.
Affiliations
  • *Department of Chemistry and Biochemistry and
  • University of Colorado Boulder (US)
ORCID
Falke, Joseph J.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2007-10-09
Volume
104
Issue
41
Pages
16176-16181
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0707719104
PMC
PMC2042181
OpenAlex
W2064638211
Cited by
151
References
0
Citations by year
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FWCI
3.18
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (R01GM063235)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
extracellular calcium influx, positive feedback loop, macrophage migration, leading edge, phosphatidylinositol 3-kinase, phosphatidylinositol 3,4,5-trisphosphate, F-actin, ruffles, chemoattractant response, protein kinase C alpha, cell polarization, leukocyte motility
MeSH terms
Actins, Animals, Cell Line, Cell Movement, Chemotaxis, Feedback, Lipopolysaccharides, Macrophages, Cell Polarity, Phosphatidylinositol 3-Kinases, Calcium Signaling, Mice, Protein Kinase C-alpha

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