CXCL mediated cell migration is facilitated by the
CXCL16 mediated cell migration is facilitated by the interaction of soluble CXCL16 with CXCR6, expressed predominantly on the cell surface of CD4+ Th1 cells, cancer infiltrating lymphocytes and platelets (Borst et al., 2012, Kim et al., 2001, Liao et al., 1997, Wilbanks et al., 2001). CXCR6 is involved in the recruitment and homing of inflammatory Genipin and proliferation and invasion of tumour cells (Galkina et al., 2007). It also participates in adhesion and chemotaxis of platelets (Borst et al., 2012), and serves as a co-receptor for HIV (Deng et al., 1997, Matloubian et al., 2000). Activation of CXCR6 by CXCL16 triggers cellular responses involving phosphatidylinositide 3-kinase (PI3K) and its downstream effector Akt (protein kinase B) (Wang et al., 2008a).
CXCL16 and CXCR6 have recently been described in cartilaginous fish (Nomiyama et al., 2011, Venkatesh et al., 2014). In humans, the CXCR6 gene resides upstream of the FYCO1 gene in chromosome 3 and is clustered with several other inflammatory chemokine receptors including XCR1, CCR1–3, CCR5, CCR8 and CCR9, CX3CR1, CCRL1 and 2, and CCBP2 (Nomiyama et al., 2011). Fig. 3 reveals that the chromosomal clustering of CXCR6 and FYCO1 in coelacanth and non-mammalian tetrapods is well conserved. However, the CXCR6 gene is absent in the two loci containing the FYCO1 gene in the zebrafish genome and to date no CXCR6 orthologues have been found in teleosts, suggesting CXCR6 may have been lost in this lineage. Interestingly, in the genome of sea lamprey (P. marinus), a jawless fish, a chemokine receptor gene with moderate sequence homology to both CXCR1/2 and CCR6 (Ensembl Acc. No.: ENSPMAP00000011202) (Table 1) is located upstream of the FYCO1 gene (Fig. 3), suggesting a common origin of CXCR1/2, CCR6, CXCR6 and other CC chemokine receptors clustered in this locus.
ACKR3/CXCR7 and other ACKRs ACKR3, also referred to as CXCR7, belongs to a group of chemokine receptors which have recently been classified by the Human Genome Organization Gene Nomenclature Committee (HGNC) and the Nomenclature Committee of the International Union of Pharmacology (IUPHAR) as atypical chemokine receptors (ACKRs) due to their inability to initiate signalling through classical G-coupled proteins (Bachelerie et al., 2013, Bachelerie et al., 2014). The ACKR family currently consists of four members, named ACKR1–4 that act as decoy receptors or scavengers for numerous CC and CXC chemokines. The ACKRs are structurally similar to the signalling chemokine receptors containing 7 transmembrane domains (Fig. 1, Fig. 4). ACKR3 is the best characterised receptor in the ACKR family. ACKR3/CXCR7 together with CXCR4, is the key player in co-ordinating the functions of the primordial chemokine CXCL12 in organ development (Thelen and Thelen, 2008), as well as the development and progression of tumours (Miao et al., 2007). ACKR3/CXCR7 forms a heterodimer with CXCR4 and/or acts alone as a scavenger for the ligand CXCL12 (Levoye et al., 2009). In zebrafish ACKR3/CXCR7 is able to initiate an endogenous, self-generated signalling gradient to direct tissue migration (Venkiteswaran et al., 2013). Increased ACKR3 expression is observed in invasive medaka melanomas and ACKR3-dependent CXCL12a/SDF-1a signalling is able to suppress melanoma growth in vivo (Liedtke et al., 2014). In addition to CXCL12, ACKR3 binds to CXCL11, an IFN-γ induced chemokine with a key role in the regulation of lymphocyte migration (Naumann et al., 2010). However, the roles of ACKR3/CXCR7 in leucocyte chemotaxis remain controversial since there are inconsistent reports about its expression in leucocytes. In zebrafish, constitutive expression of ACKR3/CXCR7 transcripts is detectable during embryogenesis and in brain neurons of adult fish. Additionally, the two ACKR3s/CXCR7s have been shown to co-ordinate cell migration in concert with CXCR4 during zebrafish development (Boldajipour et al., 2008, Cubedo et al., 2009, Valentin et al., 2007).