![]() Notably, members of the small GTPase family transmit downstream signals and thereby link chemokine receptor activation to actin cytoskeleton rearrangements required for the induction of cell polarity and locomotion. Chemokine receptors couple to heterotrimeric G-proteins of the G i class and their activation promotes the exchange of GTP for GDP on the Gα-subunit resulting in its dissociation from the βγ-subunits ( Figure 1). Chemokine binding to the receptor induces conformational changes that markedly rearrange the positions of the transmembrane helices particularly at the cytoplasmic surface of the plasma membrane allowing G-protein coupling and signal transduction ( Legler and Thelen, 2018 Weis and Kobilka, 2018). Chemokine receptors belong to the class A of G-protein coupled receptors (GPCRs) and possess seven α-helical domains that span the plasma membrane and are connected by extracellular and intracellular loops ( Legler and Thelen, 2018 Lämmermann and Kastenmüller, 2019). Locally produced chemokines can form gradients in situ that migrating cells can sense through cognate chemokine receptors ( Hughes and Nibbs, 2018). Important guidance cues are provided by the chemokine network. Leukocytes are professional migratory cells that are able to sense various guidance cues and to integrate external signals to navigate through different types of tissue and to cross blood and lymph vessels ( Nourshargh et al., 2010). In host defense, guided cell locomotion and positioning critically contributes to wound healing and cellular immune responses. Moreover, we provide an overview on the role of membrane scaffold proteins, particularly tetraspanins, flotillins/reggies, and caveolins in controlling leukocyte migration both in vitro and in vivo.Ĭell migration is essential for a number of physiological and pathophysiological processes, such as embryogenesis, organogenesis, tissue homeostasis, but also cancer malignancy. In this review we summarize recent advances made in the understanding of how membrane cholesterol levels modulate chemokine receptor signaling and hence leukocyte trafficking. This becomes evident by the fact that mislocalization of membrane proteins is known to deleteriously affect cellular functions that may cause diseases. Therefore, the composition of the membrane in concert with proteins that influence the compartmentalization of the plasma membrane or contribute to delineate intracellular signaling molecules are key in controlling leukocyte navigation. These extracellular signals must be transmitted across the leukocyte’s plasma membrane in a way that intracellular signaling cascades enable directional cell movement. Leukocytes are specialized in sensing a variety of guidance cues and to integrate environmental stimuli to navigate in a timely and spatially controlled manner. Leukocyte migration across vessels into and within peripheral and lymphoid tissues is essential for host defense against invading pathogens. 3Theodor Kocher Institute, University of Bern, Bern, Switzerland.2Faculty of Biology, University of Konstanz, Konstanz, Germany.1Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.
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