Rac1 links leading edge and uropod events through Rho and myosin activation during chemotaxis.
Chemotactic responsiveness is crucial to neutrophil recruitment to sites of infection. During chemotaxis, highly divergent cytoskeletal programs are executed at the leading and trailing edge of motile neutrophils. The Rho family of small GTPases plays a critical role in cell migration, and recent work has focused on elucidating the specific roles played by Rac1, Rac2, Cdc42, and Rho during cellular chemotaxis. Rac GTPases regulate actin polymerization and extension of the leading edge, whereas Rho GTPases control myosin-based contraction of the trailing edge. Rac and Rho signaling are thought to crosstalk with one another, and previous research has focused on mutual inhibition of Rac and Rho signaling during chemotaxis. Indeed, polarization of neutrophils has been proposed to involve the activity of a negative feedback system where Rac activation at the front of the cell inhibits local Rho activation, and vice versa. Using primary human neutrophils and neutrophils derived from a Rac1/Rac2-null transgenic mouse model, we demonstrate here that Rac1 (and not Rac2) is essential for Rho and myosin activation at the trailing edge to regulate uropod function. We conclude that Rac plays both positive and negative roles in the organization of the Rhomyosin "backness" program, thereby promoting stable polarity in chemotaxing neutrophils.
Pestonjamasp
Kersi N
KN
Departments of Immunology and Cell Biology-IMM14, The Scripps Research Institute, La Jolla, CA, USA.
Forster
Carol
C
Sun
Chunxiang
C
Gardiner
Elisabeth M
EM
Bohl
Ben
B
Weiner
Orion
O
Bokoch
Gary M
GM
Glogauer
Michael
M
D000818:Animals; D016764:Cell Polarity; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018994:Myosin Light Chains / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
D018994:Myosin Light Chains; D009218:Myosins; D009479:Neuropeptides; D011994:Recombinant Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C484602:Rac1 protein, mouse