The migration of cells through constricting spaces or along fibrous tracks in tissues is important for many biological processes and depends on the mechanical properties of a cytoskeleton made up of three different filaments: F‐actin, microtubules, and intermediate filaments. The signaling pathways and cytoskeletal structures that control cell motility on 2D are often very different from those that control motility in 3D. Previous studies have shown that intermediate filaments can promote actin‐driven protrusions at the cell edge, but have little effect on overall motility of cells on flat surfaces. They are however important for cells to maintain resistance to repeated compressive stresses that are expected to occur in vivo. Using mouse embryonic fibroblasts derived from wild‐type and vimentin‐null mice, it is found that loss of vimentin increases motility in 3D microchannels even though on flat surfaces it has the opposite effect. Atomic force microscopy and traction force microscopy experiments reveal that vimentin enhances perinuclear cell stiffness while maintaining the same level of acto‐myosin contractility in cells. A minimal model in which a perinuclear vimentin cage constricts along with the nucleus during motility through confining spaces, providing mechanical resistance against large strains that could damage the structural integrity of cells, is proposed.

Vimentin is a structural protein that is required for mesenchymal cell migration and directly interacts with actin, β1 integrin and paxillin. We examined how these interactions enable vimentin to regulate cell migration on collagen. In fibroblasts, depletion of vimentin increased talin-dependent activation of β1 integrin by >2-fold. Loss of vimentin was associated with reduction of β1 integrin clustering by 50% and inhibition of paxillin recruitment to focal adhesions by >60%, which was restored by vimentin expression. This reduction of paxillin was associated with 65% lower Cdc42 activation, a 60% reduction of cell extension formation and >35% less cell migration on collagen. The activation of PAK1, a downstream effector of Cdc42, was required for vimentin phosphorylation and filament maturation. We propose that vimentin tunes cell migration through collagen by acting as an adaptor protein for focal adhesion proteins, thereby regulating β1 integrin activation, resulting in well-organized, mature integrin clusters.

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Vimentin expression contributes to cellular mechanoprotection and is a widely recognized marker of fibroblasts and of epithelial-mesenchymal transition. But it is not understood how vimentin affects signaling that controls cell migration and extracellular matrix (ECM) remodeling. Recent data indicate that vimentin controls collagen deposition and ECM structure by regulating contractile force application to the ECM and through post-transcriptional regulation of ECM related genes. Binding of cells to the ECM promotes the association of vimentin with cytoplasmic domains of adhesion receptors such as integrins. After initial adhesion, cell-generated, myosin-dependent forces and signals that impact vimentin structure can affect cell migration. Post-translational modifications of vimentin determine its adaptor functions, including binding to cell adhesion proteins like paxillin and talin. Accordingly, vimentin regulates the growth, maturation and adhesive strength of integrin-dependent adhesions, which enables cells to tune their attachment to collagen, regulate the formation of cell extensions and control cell migration through connective tissues. Thus, vimentin tunes signaling cascades that regulate cell migration and ECM remodeling. Here we consider how specific properties of vimentin serve to control cell attachment to the underlying ECM and to regulate mesenchymal cell migration and remodeling of the ECM by resident fibroblasts.

The intermediate filament protein vimentin is a widely used phenotypic marker for identifying cells of the mesenchymal linkage such as fibroblasts and myofibroblasts, but the full repertoire of vimentin's functional attributes has not been fully explored.Here we consider how vimentin, in addition to its contributions to mechanical stabilization of cell structure, also helps to control the assembly of cell adhesions and migration through collagen matrices. While the assembly and function of matrix adhesions are critical for the differentiation of myofibroblasts and many other types of adherent cells, a potential mechanism that explains how vimentin affects the recruitment and abundance of centrally important proteins in cell adhesions has been elusive. Here we review recent data indicating that vimentin plays a central regulatory role in the assembly of focal adhesions which form in response to the attachment to collagen. We show that in particular, vimentin is a key organizer of the β1 integrin adhesive machinery, which affects cell migration through collagen. This review provides a comprehensive picture of the surprisingly broad array of processes and molecules with which vimentin interacts to affect cell function in the context of fibroblast and myofibroblast adhesion and migration on collagen.