Integrins and ion channels in cell migration: implications for neuronal development, wound healing and metastatic spread

Abstract

Cells migration is necessary for proper embryonic development and adult tissue remodeling. Its mechanisms determine the physiopathology of processes such as neuronal targeting, inflammation, wound healing and metastatic spread. Crawling of cells onto solid surfaces requires a controlled sequence of cell protrusions and retractions that mainly depends on sophisticated regulation of the actin cytoskeleton, although the contribution of microtubules should not be neglected. This process is triggered and modulated by a combination of diffusible and fixed environmental signals. External cues are sensed and integrated by membrane receptors, including integrins, which transduce these signals into cellular signaling pathways, often centered on the small GTPase proteins belonging to the Rho family. These pathways regulate the coordinated cytoskeletal rearrangements necessary for proper timing of adhesion, contraction and detachement at the front and rear side of cells finding their way through the extracellular spaces. The overall process involves continuous modulation of cell motility, shape and volume, in which ion channels play major roles. In particular, Ca2+ signals have both global and local regulatory effects on cell motility, because they target the contractile proteins as well as many regulatory proteins. After reviewing the fundamental mechanisms of eukaryotic cell migration onto solid substrates, we briefly describe how integrin receptors and ion channels are involved in cell movement. We next examine a few processes in which these mechanisms have been studied in depth. We thus illustrate how integrins and K+ channels control cell volume and migration, how intracellular Ca2+ homeostasis affects the motility of neuronal growth cones and what is known about the ion channel roles in epithelial cell migration. These mechanisms are implicated in a variety of pathological processes, such as the disruption of neural circuits and wound healing. Finally, we describe the interaction between neoplastic cells and their local environment and how derangement of adhesion can lead to metastatic spread. It is likely that the cellular mechanisms controlled by integrin receptors, ion channels or both participate in the entire metastatic process. Until now, however, evidence is limited to a few steps of the metastatic cascade, such as brain tumor invasiveness.