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Cells Move When Ions and Water Flow Pflugers Arch - Eur J Physiol (2007) 453:421–432 DOI 10.1007/s00424-006-0138-6 INVITED REVIEW Cells move when ions and water flow Albrecht Schwab & Volodymyr Nechyporuk-Zloy & Anke Fabian & Christian Stock Received: 30 June 2006 /Accepted: 9 July 2006 / Published online: 5 October 2006 # Springer-Verlag 2006 Abstract Cell migration is a process that plays an life cycle. Migration starts early on during embryogenesis. important role throughout the entire life span. It starts early After birth, cells like neuroblasts still need to move to their on during embryogenesis and contributes to shaping our final “place of work” [60]. The outgrowth of nerve growth body. Migrating cells are involved in maintaining the cones can be viewed as a special form of cell migration integrity of our body, for instance, by defending it against since the cell body of the nerve cell usually remains invading pathogens. On the other side, migration of tumor stationary [41]. Wound healing requires the movement of cells may have lethal consequences when tumors spread fibroblasts or epithelial cells. Epithelial wounds frequently metastatically. Thus, there is a strong interest in unraveling occur in the mucosa of the gastrointestinal tract, and the cellular mechanisms underlying cell migration. The migration of epithelial cells into the denuded area is a fast purpose of this review is to illustrate the functional way to reestablish epithelial integrity [20]. Other processes importance of ion and water channels as part of the cellular strongly dependent on cell migration are the responses of migration machinery. Ion and water flow is required for the immune system, angiogenesis [127], and the formation optimal migration, and the inhibition or genetic ablation of of tumor metastases [144]. Thus, migrating cells originate channels leads to a marked impairment of migration. We from a broad range of different tissues, and they fulfill briefly touch cytoskeletal mechanisms of migration as well diverse physiological and pathophysiological functions. as cell–matrix interactions. We then present some general Yet, the cellular mechanisms underlying migration of these principles by which channels can affect cell migration different cell types often follow common rules. Some of before we discuss each channel group separately. these common mechanisms will be briefly summarized before we discuss the function of ion channel activity for Keywords Aquaporins . Cell migration . Cell–matrix cell migration in more detail. interactions . Cytoskeleton . Ion channels Migrating cells are polarized Introduction All migrating cells are polarized morphologically and Cell migration is required for embryogenesis [11] and the functionally along the axis of movement [75, 86]. This is well-being of our body throughout life. On the other hand, particularly evident when cells are migrating on a two- “too much” migration or migration of the wrong cell type dimensional substrate. The front part of migrating cells is may be the cause of serious health problems or death. There formed by the so-called lamellipodium that is a fan-like, is hardly any cell that does not migrate at a given time in its 300-nm thin, and organelle-free process [1]. The cell body : : : that may extend into a uropod marks the rear part. The A. Schwab (*) V. Nechyporuk-Zloy A. Fabian C. Stock ability to maintain this polarization is a prerequisite for Institut für Physiologie II, Universität Münster, directed migration. It implies that different components of Robert-Koch-Str. 27b, 48149 Münster, Germany the cellular migration machinery are active at either cell e-mail: [email protected] pole. A repeated and coordinated cycle of protrusion of the 422 Pflugers Arch - Eur J Physiol (2007) 453:421–432 lamellipodium and retraction of the rear part of the cell will matrix [9]. Focal contacts comprise heterodimeric integrins then result in directed migration. In chemotactically composed of α and β subunits [43], the focal adhesion stimulated cells such as Dictyostelium discoideum or kinase (FAK; [122]), talin, vinculin, paxillin, and other neutrophil granulocytes, the enzymes phosphatidylinositol- proteins attached to the actin filament network [10, 147]. 3 kinase (PI3K) and phosphatase and tensin homologue in FAK becomes phosphorylated upon focal adhesion forma- chromosome 10 (PTEN) play a crucial role in maintaining tion when integrins bind to the extracellular matrix. It helps the polarity [80]. They lead to the localized accumulation of coordinate the signal transduction events activated down- phosphatidylinositol-3,4,5-triphosphate at the leading edge stream of both integrins and growth factor receptors [42]. of chemotaxing cells. That is, a shallow gradient of an The turnover of integrin-mediated adhesions, especially extracellular chemoattractant can be amplified into a steep the release of cell–matrix contacts at the rear end, is a intracellular gradient of phosphatidylinositol-3,4,5-triphos- limiting process during cell migration. Tyrosine-kinase- phate. This modulates actin remodeling at the leading edge mediated phosphorylation and proteolysis of focal adhesion and myosin II assembly at the rear part of motile cells. In components by the calpain family of intracellular proteases addition, the Na+/H+ exchanger NHE1 is also involved in contribute to the adhesion turnover [14]. Thus, calpain- maintaining the polarity of migrating cells. Accordingly, mediated cleavage of the focal adhesion component talin is NHE1-deficient cells have a severely impaired ability for involved in controlling the turnover of integrin-dependent persistent migration into one direction [18, 94, 121]. focal adhesions [28]. Another mechanism controlling cell adhesion depends on the extracellular pH and involves the activity of the Na+/H+ exchanger NHE1 [126]. As NHE1 and the integrins are colocalized at the leading edges of Cytoskeletal mechanisms of cell migration lamellipodia [19, 34, 54, 98], NHE1 creates a proton- enriched nanoenvironment in the immediate vicinity of the The cytoskeleton is probably the most important cellular focal adhesion complexes. The local pHe at focal adhesion motor for cell migration. The lamellipodium comprises a sites modulates the strength of cell adhesion and thereby dense meshwork of actin filaments [35]. They are poly- migration on a collagen I matrix [126]. A surplus of protons merizing at their plus ends into the direction of movement or a high NHE1 activity leads to a tight adhesion and and thereby protrude the plasma membrane at the leading eventually, if strong enough, to a decrease in cell migration, edge of the lamellipodium [82, 137]. Actin monomers and whereas a lack of protons due to low NHE1 activity filaments are escorted by many proteins that ensure the prevents adhesion and migration (see [125] for a review on fine-tuning of actin filament remodeling according to the the function of NHE1 in cell migration). needs of the crawling cell [141]. The Arp2/3 complex catalyses for example the nucleation of new actin filaments and the growth of existing filaments [148]. It is activated by members of the WASP/WAVE family [107]. These proteins Modulation of cell migration by ion channels are regulated by diverse factors, such as the phospholipid phosphatidylinositol-4,5 bisphosphate (PIP2), calmodulin, We will first give a general overview of possible mecha- Ca2+, and by the family of small Rho GTPases, e.g., Cdc42 nisms by which ion channel activity can modulate the or Rac, that promotes the formation of specific cellular cellular migration machinery before discussing the role of morphologies and plays a major role in cell migration [96, individual ion channels in more detail. The close interrela- 99, 146]. The retraction of the rear part of a migrating cell tion between ion channel activity and cell migration is in is mediated among others by the contraction of the cortical part due to one of the housekeeping functions that ion actomyosin network at this cell pole so that inhibition of channels exert in almost every cell. Ion channels play a myosin II leads to reduced motility of neutrophils due to pivotal role in cell volume regulation [64]. This is an defective uropod detachment [24]. important issue for cell migration since the integrity of the actin cytoskeleton is critically dependent on cell volume. Cell swelling leads to actin depolymerization, whereas cell Cell–matrix interactions during migration shrinkage promotes actin polymerization [37, 95, 119]. Thus, ion channels are crucial for creating the “correct” Coordinated formation and release of focal adhesion intracellular milieu for the optimal functioning of the contacts to the extracellular matrix mediated by integrin cytoskeletal migration machinery. The interrelation between receptor molecules are needed for cell migration [48] (for ion channel activity and cell migration becomes even more review see [139]). Focal contacts mediate the force intricate by the fact that cytoskeletal components them- transduction from the cytoskeleton onto the extracellular selves regulate ion channel activity [23, 35, 77, 90] so that Pflugers Arch - Eur J Physiol (2007) 453:421–432 423 the ability of ion channels to regulate cell volume relies on the transepithelial potential is absent [104]. Similarly, tumor an intact cytoskeleton. Another intriguing aspect is that cell migration and the sprouting of endothelial cells are some ion channels expressed in migrating cells and the affected by electric fields [85, 140]. actin cytoskeleton are regulated by
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