LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment.
This study analyzes signaling events initiated through binding of the leukocyte integrin LFA-1 to ICAM-1, which leads to T cell attachment, polarization and random migration. These events are critically dependent on dynamic changes in the acto-myosin cytoskeleton under the regulation of myosin light chain kinase and ROCK (Rho kinase). A key finding is that the activity of these two kinases is spatially segregated. Myosin light chain kinase (MLCK) must operate at the leading edge of the T cell because blocking its activity causes the polarized T cell to retract from the front of the cell. These activities are mirrored by inhibiting calmodulin, the activator of MLCK. In contrast inhibition of ROCK (and RhoA) has the effect of preventing detachment of the T cell trailing edge, showing that this kinase operates at the rear of the cell. This compartmentalized activity of the two kinases is reflected in their localization within the T cell. Myosin light chain kinase is concentrated at the leading edge, overlapping F-actin, whereas ROCK is more widely distributed in the trailing edge of the T cell. Thus these two kinases perform two different functions in the migrating T cell, with myosin light chain kinase activity important for attachment and movement at the leading edge and ROCK activity required for the detachment of the trailing edge. These two actomyosin-dependent processes operate coordinately to cause forward migration of a T cell.
Smith
Andrew
A
Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, Lincoln's Inn Fields, London WC2A 3PX, UK.
Bracke
Madelon
M
Leitinger
Birgit
B
Porter
Joanna C
JC
Hogg
Nancy
N
D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D020742:rhoA GTP-Binding Protein