Moving towards a Better Understanding of Chemotaxis

Eukaryotic cells are thought to move across supporting surfaces through a combination of coordinated processes: polarisation; extension of dynamic protrusions from a leading edge; adhesion-associated stabilisation of some protrusions; centripetal pulling against those leading adhesions; and de-adhesion at the rear. Gradients of extracellular ligands can be detected by cells and then used to guide them either towards the source (in the case of a chemoattractant) or away from the source (in the case of a chemorepellent)--such migration is termed chemotaxis. Recent work suggests that chemotaxis probably emerges from the ability of cells to spatially encode extracellular gradients of ligands, a process for which phosphoinositide 3'-kinase (PI3K) signals alone are insufficient, and to use that vectorial information to bias movement by enhancing the survival, and not the formation, of the protrusions that experience the greatest stimulation.

[1]  M. Dembo,et al.  Neutrophil traction stresses are concentrated in the uropod during migration. , 2007, Biophysical journal.

[2]  F. Maxfield,et al.  Oriented endocytic recycling of alpha5beta1 in motile neutrophils. , 2000, Blood.

[3]  M. Falasca,et al.  Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration , 2005, The Journal of cell biology.

[4]  P. Devreotes,et al.  Distinct roles of PI(3,4,5)P3 during chemoattractant signaling in Dictyostelium: a quantitative in vivo analysis by inhibition of PI3-kinase. , 2006, Molecular biology of the cell.

[5]  S. Diez,et al.  Dynamic Actin Patterns and Arp2/3 Assembly at the Substrate-Attached Surface of Motile Cells , 2004, Current Biology.

[6]  B. Heit,et al.  Fundamentally different roles for LFA-1, Mac-1 and α4-integrin in neutrophil chemotaxis , 2005, Journal of Cell Science.

[7]  C. Downes,et al.  The pleckstrin homology domains of protein kinase B and GRP1 (general receptor for phosphoinositides-1) are sensitive and selective probes for the cellular detection of phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 3,4,5-trisphosphate in vivo. , 1999 .

[8]  Marc W Kirschner,et al.  An Actin-Based Wave Generator Organizes Cell Motility , 2007, PLoS biology.

[9]  Hui Ma,et al.  Chemoattractant‐mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium , 1999, The EMBO journal.

[10]  Hervé Guillou,et al.  Gbetagammas and the Ras binding domain of p110gamma are both important regulators of PI(3)Kgamma signalling in neutrophils. , 2006, Nature cell biology.

[11]  Dianqing Wu,et al.  Roles of PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction , 2000 .

[12]  M. Abercrombie,et al.  The locomotion of fibroblasts in culture. 3. Movements of particles on the dorsal surface of the leading lamella. , 1970, Experimental cell research.

[13]  T. Mak,et al.  Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1 , 2007, Nature Cell Biology.

[14]  R. Kay,et al.  Chemotaxis in the Absence of PIP3 Gradients , 2007, Current Biology.

[15]  C. Tseng,et al.  A Requirement for Phosphatidylinositol 3-Kinase in Pseudopod Extension* , 1999, The Journal of Biological Chemistry.

[16]  J W Sedat,et al.  Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. , 1999, Molecular biology of the cell.

[17]  P. Lipp,et al.  Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. , 2002, Molecular cell.

[18]  P. V. van Haastert,et al.  Phospholipase C regulation of phosphatidylinositol 3,4,5-trisphosphate-mediated chemotaxis. , 2007, Molecular biology of the cell.

[19]  W L Stanford,et al.  Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. , 2000, Science.

[20]  H. Bourne,et al.  Pertussis toxin inhibition of chemotactic factor-induced calcium mobilization and function in human polymorphonuclear leukocytes , 1985, The Journal of experimental medicine.

[21]  Richard A. Firtel,et al.  Role of Phosphatidylinositol 3′ Kinase and a Downstream Pleckstrin Homology Domain–Containing Protein in Controlling Chemotaxis inDictyostelium , 2001, The Journal of cell biology.

[22]  S. Leevers,et al.  Input from Ras is required for maximal PI(3)K signalling in Drosophila , 2006, Nature Cell Biology.

[23]  S. Zigmond Beginning and ending an actin filament: control at the barbed end. , 2004, Current topics in developmental biology.

[24]  M. Lemmon,et al.  Pleckstrin homology (PH) domains and phosphoinositides. , 2007, Biochemical Society symposium.

[25]  G. Stamp,et al.  Binding of Ras to Phosphoinositide 3-Kinase p110α Is Required for Ras- Driven Tumorigenesis in Mice , 2007, Cell.

[26]  W. T. Chen Mechanism of retraction of the trailing edge during fibroblast movement , 1981, The Journal of cell biology.

[27]  George Oster,et al.  Polymer Motors: Pushing out the Front and Pulling up the Back , 2003, Current Biology.

[28]  K. Okkenhaug,et al.  Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. , 2005, Blood.

[29]  M. Sheetz,et al.  Periodic Lamellipodial Contractions Correlate with Rearward Actin Waves , 2004, Cell.

[30]  P. Kubes,et al.  Leukocyte PI3Kgamma and PI3Kdelta have temporally distinct roles for leukocyte recruitment in vivo. , 2007, Blood.

[31]  Richard A. Firtel,et al.  Spatial and Temporal Regulation of 3-Phosphoinositides by PI 3-Kinase and PTEN Mediates Chemotaxis , 2002, Cell.

[32]  P. Devreotes,et al.  Gene targeting of the aggregation stage cAMP receptor cAR1 in Dictyostelium. , 1991, Genes & development.

[33]  Kevan M. Shokat,et al.  To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front , 2006, The Journal of cell biology.

[34]  D. Yamazaki,et al.  PtdIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia , 2004, Nature Cell Biology.

[35]  Z. Li,et al.  Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. , 2000, Science.

[36]  C. Parent,et al.  Localization of the G Protein βγ Complex in Living Cells During Chemotaxis , 2000 .

[37]  R T Tranquillo,et al.  A stochastic model for leukocyte random motility and chemotaxis based on receptor binding fluctuations , 1988, The Journal of cell biology.

[38]  P. Devreotes,et al.  Tumor Suppressor PTEN Mediates Sensing of Chemoattractant Gradients , 2002, Cell.

[39]  M. Schaefer,et al.  Characterization of p87PIKAP, a Novel Regulatory Subunit of Phosphoinositide 3-Kinase γ That Is Highly Expressed in Heart and Interacts with PDE3B* , 2006, Journal of Biological Chemistry.

[40]  T. Sasazuki,et al.  DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis , 2006, The Journal of cell biology.

[41]  Christopher V. Rao,et al.  A Mathematical Model for Neutrophil Gradient Sensing and Polarization , 2007, PLoS Comput. Biol..

[42]  T. Meyer,et al.  A local coupling model and compass parameter for eukaryotic chemotaxis. , 2005, Developmental cell.

[43]  J. Small,et al.  The comings and goings of actin: coupling protrusion and retraction in cell motility. , 2005, Current opinion in cell biology.

[44]  S. Zigmond,et al.  Chemoattractant stimulation of polymorphonuclear leucocyte locomotion. , 1990, Seminars in cell biology.

[45]  P. Finan,et al.  PI(3)Kgamma has an important context-dependent role in neutrophil chemokinesis. , 2007, Nature cell biology.

[46]  T. Pollard,et al.  Cellular Motility Driven by Assembly and Disassembly of Actin Filaments , 2003, Cell.

[47]  P. Hawkins,et al.  p84, a new Gbetagamma-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110gamma. , 2005, Current biology : CB.

[48]  M. Bretscher,et al.  Circulation of the plasma membrane in Dictyostelium. , 1999, Molecular biology of the cell.

[49]  R. Firtel,et al.  Regulation and function of G alpha protein subunits in Dictyostelium. , 1989, Cell.

[50]  R. Firtel,et al.  Receptor-mediated regulation of PI3Ks confines PI(3,4,5)P3 to the leading edge of chemotaxing cells. , 2003, Molecular biology of the cell.

[51]  C. Garlanda,et al.  Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. , 2000, Science.

[52]  P. Hawkins,et al.  P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. , 2002, Cell.

[53]  Richard A. Firtel,et al.  Rap1 controls cell adhesion and cell motility through the regulation of myosin II , 2007, The Journal of cell biology.

[54]  P. Iglesias,et al.  PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis. , 2007, Developmental cell.

[55]  P. V. van Haastert,et al.  A Diverse Family of Inositol 5-Phosphatases Playing a Role in Growth and Development in Dictyostelium discoideum * 210 , 2003, The Journal of Biological Chemistry.

[56]  G. Paré,et al.  Class IA Phosphatidylinositide 3-Kinases, rather than p110γ, Regulate Formyl-Methionyl-Leucyl-Phenylalanine-Stimulated Chemotaxis and Superoxide Production in Differentiated Neutrophil-Like PLB-985 Cells1 , 2006, The Journal of Immunology.

[57]  J. Small,et al.  Microfilament-based motility in non-muscle cells. , 1989, Current opinion in cell biology.

[58]  P. Devreotes,et al.  Receptor-Mediated Activation of Heterotrimeric G-Proteins in Living Cells , 2001, Science.

[59]  G. Shaulsky,et al.  CRAC, a cytosolic protein containing a pleckstrin homology domain, is required for receptor and G protein-mediated activation of adenylyl cyclase in Dictyostelium , 1994, The Journal of cell biology.

[60]  T. Molski,et al.  Pertussis but not cholera toxin inhibits the stimulated increase in actin association with the cytoskeleton in rabbit neutrophils: role of the "G proteins" in stimulus-response coupling. , 1985, Biochemical and biophysical research communications.

[61]  P. Hawkins,et al.  Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. , 2002, Current opinion in cell biology.

[62]  O. Florey,et al.  The class II phosphoinositide 3‐kinase PI3K‐C2β regulates cell migration by a PtdIns(3)P dependent mechanism , 2005, Journal of cellular physiology.

[63]  G. Laevsky,et al.  Cross-linking of actin filaments by myosin II is a major contributor to cortical integrity and cell motility in restrictive environments , 2003, Journal of Cell Science.

[64]  P. Hawkins,et al.  p84, a New Gβγ-Activated Regulatory Subunit of the Type IB Phosphoinositide 3-Kinase p110γ , 2005, Current Biology.

[65]  Silvano Sozzani,et al.  Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation , 2000 .

[66]  D. Cantrell,et al.  Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse , 2002, Nature Immunology.

[68]  R. Firtel,et al.  A Dictyostelium homologue of WASP is required for polarized F-actin assembly during chemotaxis. , 2005, Molecular biology of the cell.

[69]  Natalie Andrew,et al.  Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions , 2007, Nature Cell Biology.

[70]  C. Parent,et al.  Localization of the G protein betagamma complex in living cells during chemotaxis. , 2000, Science.

[71]  Richard A. Firtel,et al.  Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement , 2004, The Journal of cell biology.

[72]  Linda Yip,et al.  ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors , 2006, Science.

[73]  P. V. van Haastert,et al.  Cyclic AMP signalling in Dictyostelium: G‐proteins activate separate Ras pathways using specific RasGEFs , 2007, EMBO reports.

[74]  G. Danuser,et al.  Two Distinct Actin Networks Drive the Protrusion of Migrating Cells , 2004, Science.

[75]  P. Hawkins,et al.  The Gβγ Sensitivity of a PI3K Is Dependent upon a Tightly Associated Adaptor, p101 , 1997, Cell.

[76]  J W Sedat,et al.  Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. , 2000, Science.

[77]  Richard A. Firtel,et al.  G protein–independent Ras/PI3K/F-actin circuit regulates basic cell motility , 2007, The Journal of cell biology.

[78]  D. Murphy,et al.  Dynamic Distribution of Chemoattractant Receptors in Living Cells During Chemotaxis and Persistent Stimulation , 1997, Journal of Cell Biology.

[79]  Thomas D Pollard,et al.  Cellular Motility Driven by Assembly and Disassembly of Actin Filaments , 2003, Cell.

[80]  R. Firtel,et al.  Regulation and function of Gα protein subunits in Dictyostelium , 1989, Cell.

[81]  Marc W. Kirschner,et al.  A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity , 2002, Nature Cell Biology.

[82]  B. Heit,et al.  An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients , 2002, The Journal of cell biology.

[83]  S. Dowler,et al.  Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. , 2000, The Biochemical journal.

[84]  Olivier Pertz,et al.  Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[85]  P. Hawkins,et al.  The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. , 1997, Cell.

[86]  R. Kay,et al.  Possible roles of the endocytic cycle in cell motility , 2007, Journal of Cell Science.

[87]  S. Colgan,et al.  Phosphoinositide 3-kinase modulation of beta(3)-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration. , 2001, Blood.

[88]  Yue Zhang,et al.  Regulation of Cell Polarity and Protrusion Formation by Targeting RhoA for Degradation , 2003, Science.

[89]  Jingsong Xu,et al.  Divergent Signals and Cytoskeletal Assemblies Regulate Self-Organizing Polarity in Neutrophils , 2003, Cell.

[90]  S. Cook Faculty Opinions recommendation of Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. , 2007 .

[91]  H. El-Samad,et al.  Bound attractant at the leading vs. the trailing edge determines chemotactic prowess , 2007, Proceedings of the National Academy of Sciences.

[92]  P. Devreotes,et al.  Signaling pathways mediating chemotaxis in the social amoeba, Dictyostelium discoideum. , 2006, European journal of cell biology.

[93]  C. Parent,et al.  A cell's sense of direction. , 1999, Science.

[94]  S. Ravid,et al.  Polarization of Myosin II Heavy Chain-Protein Kinase C in Chemotaxing Dictyostelium Cells* , 2002, The Journal of Biological Chemistry.

[95]  Gaudenz Danuser,et al.  Differential Transmission of Actin Motion Within Focal Adhesions , 2007, Science.

[96]  S. Gygi,et al.  Hem-1 Complexes Are Essential for Rac Activation, Actin Polymerization, and Myosin Regulation during Neutrophil Chemotaxis , 2006, PLoS biology.

[97]  D. Dormann,et al.  In vivo analysis of 3-phosphoinositide dynamics during Dictyostelium phagocytosis and chemotaxis , 2004, Journal of Cell Science.

[98]  E. Evans,et al.  Mechanical properties of the red cell membrane in relation to molecular structure and genetic defects. , 1994, Annual review of biophysics and biomolecular structure.

[99]  Fabio Apone,et al.  Rac regulation of chemotaxis and morphogenesis in Dictyostelium , 2004, The EMBO journal.

[100]  J. Penninger,et al.  The role of endothelial PI3Kgamma activity in neutrophil trafficking. , 2005, Blood.

[101]  R. Firtel,et al.  Role of Phosphatidylinositol 3-Kinases in Chemotaxis in Dictyostelium* , 2007, Journal of Biological Chemistry.

[102]  V. Niggli,et al.  A membrane‐permeant ester of phosphatidylinositol 3,4,5‐trisphosphate (PIP3) is an activator of human neutrophil migration , 2000, FEBS letters.

[103]  P. V. van Haastert,et al.  Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis , 2007, The Journal of cell biology.

[104]  V. Niggli,et al.  The phosphatidylinositol 3-kinase inhibitor wortmannin markedly reduces chemotactic peptide-induced locomotion and increases in cytoskeletal actin in human neutrophils. , 1997, European journal of pharmacology.

[105]  J. Spudich,et al.  Disruption of the Dictyostelium myosin heavy chain gene by homologous recombination. , 1987, Science.

[106]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[107]  Wei Lu,et al.  Directional Sensing Requires Gβγ-Mediated PAK1 and PIXα-Dependent Activation of Cdc42 , 2003, Cell.

[108]  Paul Herzmark,et al.  Morphology matters in immune cell chemotaxis: membrane asymmetry affects amplification , 2006, Physical biology.

[109]  D. Murphy,et al.  G Protein Signaling Events Are Activated at the Leading Edge of Chemotactic Cells , 1998, Cell.

[110]  M. Abercrombie,et al.  The locomotion of fibroblasts in culture. II. "RRuffling". , 1970, Experimental cell research.

[111]  F. Maxfield,et al.  Oriented endocytic recycling of α5β1 in motile neutrophils , 2000 .