Editors' ChoiceCell Migration

Moving in 2D Versus 3D

Science Signaling  07 Sep 2010:
Vol. 3, Issue 138, pp. ec274
DOI: 10.1126/scisignal.3138ec274

T cells encounter both two-dimensional (2D) conditions (endothelial cell surfaces of the circulatory system) and three-dimensional (3D) conditions (interstitial extracellular matrix of tissues) as they migrate through the body to perform their immunosurveillance functions and respond to cues indicating infection. Migration in 2D conditions involves an integrin-dependent protrusion-adhesion-contraction process mediated by the actin-myosin cytoskeleton, whereas constant actin flow through continuous actin treadmilling underlies T cell movement in the 3D tissue environment (see Weber and Sixt). Klemke et al. found that T cells growing on a 2D surface (coated coverslip) and exposed to the chemokine SDF-1 exhibited activation of the guanosine triphosphatase Ras at their leading edges. Inhibition of Ras activation with a dominant-negative mutant prevented SDF-1–mediated activation of MEK (mitogen-activated protein kinase kinase), ERK (extracellular signal–regulated protein kinase), LIMK1 (LIM kinase 1) dephosphorylation, and dephosphorylation of cofilin, which activated this filamentous actin-severing and -depolymerizing protein. (LIMK1 is responsible for phosphorylating and inhibiting cofilin.) In primary human T cells, cofilin was present throughout the actin cytoskeleton (leading edge, central region, and trailing uropod), suggesting that localized activation of the Ras pathway controls its activity. Comparison of T cells migrating in a 2D or 3D culture environment showed that the dominant-negative Ras mutant inhibited migration more profoundly in the 3D situation. Inhibition of MEK or knockdown of cofilin reduced 3D migration without inhibiting 2D migration of T cells. Addition of the myosin II blocker blebbistatin, which forces cells to migrate by actin flow instead of actin-myosin contraction, sensitized T cells migrating in 2D conditions to inhibition of MEK. Thus, T cells have two Ras-dependent mechanisms of migration, and cofilin-mediated filamentous actin depolymerization is critical for movement in a 3D environment.

M. Klemke, E. Kramer, M. H. Konstandin, G. H. Wabnitz, Y. Samstag, An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environments. EMBO J. 29, 2915–2929 (2010). [PubMed]

M. Weber, M. Sixt, MEK signalling tunes actin treadmilling for interstitial lymphocyte migration. EMBO J. 29, 2861–2863 (2010). [PubMed]