Erschienen:
[Erscheinungsort nicht ermittelbar]: Università degli Studi di Milano, 2014
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, Università degli Studi di Milano, 2014
Anmerkungen:
Beschreibung:
Chemokines promote leukocyte migration through the activation of dedicated G-protein coupled receptors. Beyond conventional chemokine receptors, which directly induce cell migration through heterotrimeric Gαi-mediated signalling events, a set of atypical chemokine receptors (ACKRs) have been described. ACKRs do not activate Gαi-mediated signalling activity, but they are mainly involved in shaping the chemokine gradient. The best characterized member of this family is ACKR2. ACKR2, previously referred to as D6, is a scavenger receptor that binds with high affinity to 13 inflammatory CC chemokines. The scavenging activity of ACKR2 relies on its intracellular traffic properties. Under homeostatic conditions, ACKR2 is mainly localized in intracellular stores associated with both early Rab4/5-positive and recycling Rab11-positive endosomes. At increasing levels of chemokines, ACKR2 increases plasma membrane abundance through an acceleration in the rate of Rab11-depedent recycling pathway, in order to optimize its chemokine scavenging activity. Here, I demonstrated that the intracellular distribution of ACKR2 is maintained by cytoskeletal dynamics. After chemokine engagement, ACKR2 activate a G-protein-independent and β-arrestin-dependent Rac1-PAK1-LIMK1 signalling cascade to finely regulate the actin cytoskeletal and the microtubules network reorganization, to promote receptor up-regulation and scavenging function. ACKR2 is able to recruit and associates both β-arrestins in basal condition, at membrane and intracellular levels, but only β-arrestin1 is recruited after active ligand stimulation, in order to promote a β-arrestin1-dependent signalling pathway, required for supporting the myosin Vb-dependent ACKR2 up-regulation and scavenging properties.