Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils.
Like neutrophilic leukocytes, differentiated HL-60 cells respond to chemoattractant by adopting a polarized morphology, with F-actin in a protruding pseudopod at the leading edge and contractile actin-myosin complexes at the back and sides. Experiments with pharmacological inhibitors, toxins, and mutant proteins show that this polarity depends on divergent, opposing "frontness" and "backness" signals generated by different receptor-activated trimeric G proteins. Frontness depends upon Gi-mediated production of 3'-phosphoinositol lipids (PI3Ps), the activated form of Rac, a small GTPase, and F-actin. G12 and G13 trigger backness signals, including activation of a second GTPase (Rho), a Rho-dependent kinase, and myosin II. Functional incompatibility causes the two resulting actin assemblies to aggregate into separate domains, making the leading edge more sensitive to attractant than the back. The latter effect explains both the neutrophil's ability to polarize in uniform concentrations of chemoattractant and its response to reversal of an attractant gradient by performing a U-turn.
Xu
Jingsong
J
Department of Cellular and Molecular Pharmacology and The Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Wang
Fei
F
Van Keymeulen
Alexandra
A
Herzmark
Paul
P
Straight
Aaron
A
Kelly
Kathleen
K
Takuwa
Yoh
Y
Sugimoto
Naotoshi
N
Mitchison
Timothy
T
Bourne
Henry R
HR
D016764:Cell Polarity / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D003599:Cytoskeleton / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D024462:Myosin Type II / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D037342:Pertussis Toxin / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011554:Pseudopodia / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester; D037342:Pertussis Toxin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D024462:Myosin Type II; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein