A role for the Rho-p160 Rho coiled-coil kinase axis in the chemokine stromal cell-derived factor-1alpha-induced lymphocyte actomyosin and microtubular organization and chemotaxis.
The possible involvement of the Rho-p160ROCK (Rho coiled-coil kinase) pathway in the signaling induced by the chemokine Stromal cell-derived factor (SDF)-1alpha has been studied in human PBL. SDF-1alpha induced activation of RhoA, but not that of Rac. RhoA activation was followed by p160ROCK activation mediated by RhoA, which led to myosin light chain (MLC) phosphorylation, which was dependent on RhoA and p160ROCK activities. The kinetics of MLC activation was similar to that of RhoA and p160ROCK. The role of this cascade in overall cell morphology and functional responses to the chemokine was examined employing different chemical inhibitors. Inhibition of either RhoA or p160ROCK did not block SDF-1alpha-induced short-term actin polymerization, but induced the formation of long spikes arising from the cell body, which were found to be microtubule based. This morphological change was associated with an increase in microtubule instability, which argues for an active microtubule polymerization in the formation of these spikes. Inhibition of the Rho-p160ROCK-MLC kinase signaling cascade at different steps blocked lymphocyte migration and the chemotaxis induced by SDF-1alpha. Our results indicate that the Rho-p160ROCK axis plays a pivotal role in the control of the cell shape as a step before lymphocyte migration toward a chemotactic gradient.
Vicente-Manzanares
Miguel
M
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, c/Diego de León, 62, E-28006 Madrid, Spain.
Cabrero
José Román
JR
Rey
Mercedes
M
Pérez-Martínez
Manuel
M
Ursa
Angeles
A
Itoh
Kazuyuki
K
Sánchez-Madrid
Francisco
F
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001905:Botulinum Toxins; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008870:Microtubules / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000648:ultrastructure; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D000577:Amides; D001381:Azepines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018994:Myosin Light Chains; D009281:Naphthalenes; D011725:Pyridines; D019718:Receptors, CXCR4; C070571:ML 7; C108830:Y 27632; D000205:Actomyosin; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein