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PMID: 15534002 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement.

The Journal of cell biology ·Vol. 167 ·No. 3 ·2004-11-08 ·Pages 505-18

Sasaki AT, Chun C, Takeda K, Firtel RA

Abstract

During chemotaxis, receptors and heterotrimeric G-protein subunits are distributed and activated almost uniformly along the cell membrane, whereas PI(3,4,5)P(3), the product of phosphatidylinositol 3-kinase (PI3K), accumulates locally at the leading edge. The key intermediate event that creates this strong PI(3,4,5)P(3) asymmetry remains unclear. Here, we show that Ras is rapidly and transiently activated in response to chemoattractant stimulation and regulates PI3K activity. Ras activation occurs at the leading edge of chemotaxing cells, and this local activation is independent of the F-actin cytoskeleton, whereas PI3K localization is dependent on F-actin polymerization. Inhibition of Ras results in severe defects in directional movement, indicating that Ras is an upstream component of the cell's compass. These results support a mechanism by which localized Ras activation mediates leading edge formation through activation of basal PI3K present on the plasma membrane and other Ras effectors required for chemotaxis. A feedback loop, mediated through localized F-actin polymerization, recruits cytosolic PI3K to the leading edge to amplify the signal.

MeSH Terms
Actins/metabolism Animals Cell Polarity Chemotaxis Dictyostelium Feedback, Physiological Humans Microscopy, Video Phosphatidylinositol 3-Kinases/metabolism Protein Transport Protozoan Proteins Signal Transduction ras Proteins/metabolism,physiology
Chemicals
Actins Protozoan Proteins Phosphatidylinositol 3-Kinases ras Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Sasaki Atsuo T
Section of Cell and Developmental Biology, Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093, USA.
Chun Cheryl
Takeda Kosuke
Firtel Richard A
References (43)
43 references, click to expand
  1. Ras proteins: different signals from different locations.
    Nat Rev Mol Cell Biol. 2003 May;4(5):373-84 PMID: 12728271
  2. A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium.
    Mol Biol Cell. 1999 Sep;10(9):2829-45 PMID: 10473630
  3. Localization of the G protein betagamma complex in living cells during chemotaxis.
    Science. 2000 Feb 11;287(5455):1034-6 PMID: 10669414
  4. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis.
    Science. 2000 Feb 11;287(5455):1037-40 PMID: 10669415
  5. A membrane-permeant ester of phosphatidylinositol 3,4, 5-trisphosphate (PIP(3)) is an activator of human neutrophil migration.
    FEBS Lett. 2000 May 12;473(2):217-21 PMID: 10812078
  6. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma.
    Cell. 2000 Dec 8;103(6):931-43 PMID: 11136978
  7. A novel Dictyostelium RasGEF is required for normal endocytosis, cell motility and multicellular development.
    Curr Biol. 2000 Nov 16;10(22):1427-37 PMID: 11102804
  8. Receptor-mediated activation of heterotrimeric G-proteins in living cells.
    Science. 2001 Mar 23;291(5512):2408-11 PMID: 11264536
  9. Role of phosphatidylinositol 3' kinase and a downstream pleckstrin homology domain-containing protein in controlling chemotaxis in dictyostelium.
    J Cell Biol. 2001 May 14;153(4):795-810 PMID: 11352940
  10. Recruitment of a myosin heavy chain kinase to actin-rich protrusions in Dictyostelium.
    Curr Biol. 2001 May 1;11(9):708-13 PMID: 11369235
  11. Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa.
    Mol Cell. 2001 May;7(5):937-47 PMID: 11389841
  12. Nonradioactive determination of Ras-GTP levels using activated ras interaction assay.
    Methods Enzymol. 2001;333:333-42 PMID: 11400349
  13. Spatio-temporal images of growth-factor-induced activation of Ras and Rap1.
    Nature. 2001 Jun 28;411(6841):1065-8 PMID: 11429608
  14. RasC is required for optimal activation of adenylyl cyclase and Akt/PKB during aggregation.
    EMBO J. 2001 Aug 15;20(16):4490-9 PMID: 11500376
  15. Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis.
    Cell. 2002 May 31;109(5):611-23 PMID: 12062104
  16. Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit.
    Cancer Cell. 2002 Mar;1(2):181-91 PMID: 12086876
  17. Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils.
    Nat Cell Biol. 2002 Jul;4(7):513-8 PMID: 12080345
  18. A PtdInsP(3)- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity.
    Nat Cell Biol. 2002 Jul;4(7):509-13 PMID: 12080346
  19. Activation of phosphoinositide 3-kinase gamma by Ras.
    Curr Biol. 2002 Jul 9;12(13):1068-75 PMID: 12121613
  20. Temporal and spatial regulation of chemotaxis.
    Dev Cell. 2002 Oct;3(4):469-78 PMID: 12408799
  21. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control.
    Mol Cell. 2002 Sep;10(3):457-68 PMID: 12408816
  22. RhoA and ROCK promote migration by limiting membrane protrusions.
    J Biol Chem. 2003 Apr 11;278(15):13578-84 PMID: 12574166
  23. Signaling pathways controlling cell polarity and chemotaxis.
    Trends Biochem Sci. 2001 Sep;26(9):557-66 PMID: 11551793
  24. Ras signalling on the endoplasmic reticulum and the Golgi.
    Nat Cell Biol. 2002 May;4(5):343-50 PMID: 11988737
  25. A function for phosphoinositide 3-kinase beta lipid products in coupling beta gamma to Ras activation in response to lysophosphatidic acid.
    J Biol Chem. 2002 Jun 14;277(24):21167-78 PMID: 11916960
  26. Tumor suppressor PTEN mediates sensing of chemoattractant gradients.
    Cell. 2002 May 31;109(5):599-610 PMID: 12062103
  27. Receptor-mediated regulation of PI3Ks confines PI(3,4,5)P3 to the leading edge of chemotaxing cells.
    Mol Biol Cell. 2003 May;14(5):1913-22 PMID: 12802064
  28. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils.
    Cell. 2003 Jul 25;114(2):201-14 PMID: 12887922
  29. Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.
    Cell. 2003 Jul 25;114(2):215-27 PMID: 12887923
  30. Leading the way: Directional sensing through phosphatidylinositol 3-kinase and other signaling pathways.
    J Cell Sci. 2003 Sep 1;116(Pt 17):3471-8 PMID: 12893811
  31. Cytoskeletal regulation by Dictyostelium Ras subfamily proteins.
    J Muscle Res Cell Motil. 2002;23(7-8):729-36 PMID: 12952071
  32. Two phases of actin polymerization display different dependencies on PI(3,4,5)P3 accumulation and have unique roles during chemotaxis.
    Mol Biol Cell. 2003 Dec;14(12):5028-37 PMID: 14595116
  33. Novel mechanism of PTEN regulation by its phosphatidylinositol 4,5-bisphosphate binding motif is critical for chemotaxis.
    J Biol Chem. 2004 Apr 16;279(16):16606-13 PMID: 14764604
  34. Chemoattractant-induced Ras activation during Dictyostelium aggregation.
    EMBO Rep. 2004 Jun;5(6):602-6 PMID: 15143344
  35. Rac regulation of chemotaxis and morphogenesis in Dictyostelium.
    EMBO J. 2004 Oct 27;23(21):4177-89 PMID: 15470506
  36. Cell motility and chemotaxis in Dictyostelium amebae lacking myosin heavy chain.
    Dev Biol. 1988 Jul;128(1):164-77 PMID: 2838348
  37. Relationship of pseudopod extension to chemotactic hormone-induced actin polymerization in amoeboid cells.
    J Cell Biochem. 1988 Jul;37(3):285-99 PMID: 3410887
  38. The aimless RasGEF is required for processing of chemotactic signals through G-protein-coupled receptors in Dictyostelium.
    Curr Biol. 1996 Jun 1;6(6):719-29 PMID: 8793298
  39. Dictyostelium RasG is required for normal motility and cytokinesis, but not growth.
    J Cell Biol. 1997 Aug 11;138(3):605-14 PMID: 9245789
  40. G protein signaling events are activated at the leading edge of chemotactic cells.
    Cell. 1998 Oct 2;95(1):81-91 PMID: 9778249
  41. Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium.
    EMBO J. 1999 Apr 15;18(8):2092-105 PMID: 10205164
  42. A cell's sense of direction.
    Science. 1999 Apr 30;284(5415):765-70 PMID: 10221901
  43. PAKa, a putative PAK family member, is required for cytokinesis and the regulation of the cytoskeleton in Dictyostelium discoideum cells during chemotaxis.
    J Cell Biol. 1999 Nov 1;147(3):559-76 PMID: 10545500
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200406177
Published
2004-11-08
Pages
505-18
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172490
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200406177 PMC Full Text View journal details
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