An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environments.
T cells infiltrate peripheral tissues to execute immunosurveillance and effector functions. For this purpose, T cells first migrate on the two-dimensional (2D) surface of endothelial cells to undergo transendothelial migration. Then they change their mode of movement to undergo migration within the three-dimensional (3D)-extracellular matrix of the infiltrated tissue. As yet, no molecular mechanisms are known, which control migration exclusively in either 2D or 3D environments. Here, we describe a signalling module that controls T-cell chemotaxis specifically in 3D environments. In chemotaxing T cells, Ras activity is spatially restricted to the lamellipodium. There, Ras initiates activation of MEK, which in turn inhibits LIM-kinase 1 activity, thereby allowing dephosphorylation of the F-actin-remodelling protein cofilin. Interference with this MEK-cofilin module by either inhibition of MEK or by knockdown of cofilin reduces speed and directionality of chemotactic migration in 3D-extracellular matrices, but not on 2D substrates. This MEK-cofilin module may have an important function in the tissue positioning of T cells during an immune response.
Klemke
Martin
M
Institute for Immunology, University of Heidelberg, Heidelberg, Germany. klemke@uni-heidelberg.de
Kramer
Elisabeth
E
Konstandin
Mathias H
MH
Wabnitz
Guido H
GH
Samstag
Yvonne
Y
D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D055785:Gene Knockdown Techniques; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
D051339:Actin Depolymerizing Factors; D000199:Actins; D019707:Receptors, Chemokine; D054461:Lim Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020559:Monomeric GTP-Binding Proteins