Emerging roles of atypical chemokine receptor 3 (ACKR3) in normal development and physiology

Abstract

The discovery that atypical chemokine receptors (ACKRs) can initiate alternative signaling pathways rather than classical G-protein coupled receptor (GPCR) signaling has changed the paradigm of chemokine receptors and their roles in modulating chemotactic responses. The ACKR family has grown over the years, with discovery of new functions and roles in a variety of pathophysiological conditions. However, the extent to which these receptors regulate normal physiology is still continuously expanding. In particular, atypical chemokine receptor 3 (ACKR3) has proven to be an important receptor in mediating normal biological functions, including cardiac development and migration of cortical neurons. In this review, we illustrate the versatile and intriguing role of ACKR3 in physiology.

Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells

“…Unlike CXCR4, CXCR7 is a non-classical GPCR that is unable to activate G proteins. The function of CXCR7 is considered to be mediated by: (a) recruiting β-arrestin-2; (b) heterodimerizing with CXCR4; and (c) acting as a “scavenger” of CXCL12, thus lowering the level of CXCL12 to regulate the activity of CXCR4 [ 28 , 29 ].…”

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

“…The two main receptors for CXCL12 are CXCR4, a ligand concentration biased G-protein coupled receptor (GPCR), and CXCR7 (AKA -Atypical Chemokine Receptor 3 or ACKR3), a β-arrestin associated receptor that has a 1000-fold higher affinity for CXCL12 than CXCR4 (Quinn, et al, 2018;Reid, et al, 2018;Sanchez-Martin, et al, 2012). Data suggests that both receptors can homodimerize, as well as heterodimerize with each other, or with other receptors including α1A/B-adrenoceptors (Decaillot, et Levoye, et al, 2009;Tripathi, et al, 2015).…”

The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides

“…One such atypical chemokine receptor, ACKR3 (formerly CXCR7), is expressed in numerous regions of the CNS and in the adrenal glands but also on endothelial cells and diverse immune cells [21][22][23] . It plays crucial roles in neuronal and cardiovascular development and in the migration of hematopoietic stem cells 24,25 . The functions of ACKR3 are proposed to mainly rely on arrestin recruitment, which is indicative of ACKR3 activation, while its signaling capacity remains highly debated and may be cell-context-dependent [26][27][28][29] .…”