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Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives.

Pawig L, Klasen C, Weber C, Bernhagen J, Noels H - Front Immunol (2015)

Bottom Line: This has complicated the understanding of CXCR4-mediated signaling and associated biological processes.Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4.Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University , Aachen , Germany.

ABSTRACT
CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus) and human β3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.

No MeSH data available.


Related in: MedlinePlus

The signaling network induced by the non-canonical CXCR4 ligands MIF, extracellular ubiquitin, and gp120. (A) MIF induces signal transduction by binding to the CXCR4, which can form a receptor complex with CD74 under certain conditions, or by binding to the atypical chemokine receptor 3 (ACKR3) (previously called CXCR7). MIF binding to CXCR4 triggers cytosolic Ca2+ influx, integrin activation, and ZAP-70 activation via Gαi, resulting in cell adhesion, migration, proliferation, and GRK2 expression. By binding to the CXCR4/CD74 signaling complex, MIF activates ERK1/2 and AKT signaling promoting cell survival and proliferation. Additionally, the MIF–CXCR4/CD74 interaction promotes JNK phosphorylation, which results in enhanced CXCL8 expression. By binding to ACKR3 MIF induces platelet survival via the activation of PI3K and AKT. (B) By binding to CXCR4, ubiquitin induces the migration of cancer as well as THP1 cells through the activation of Gαi-dependent PLC-induced Ca2+ influx, MAPK, and AKT phosphorylation. The HIV glycoprotein gp120 uses CXCR4 as co-receptor for fusion of viral and host cell membrane, which results in HIV infection. In addition, gp120 can induce cell death via CXCR4 by activating caspases, p53-dependent cytochrome C release, and PI3K/AKT-dependent Fas ligand expression. AKT, protein kinase B; Ca2+, calcium ions; Cyt. C, cytochrome C; ERK1/2, extracellular signal-regulated kinases 1/2; Gαi, Gi-protein subunit α; gp120, glycoprotein 120; GRK2, G protein-coupled receptor kinase 2; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MIF, macrophage migration inhibitory factor; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; THP1, monocytic cell line; ZAP-70, zeta-chain-associated protein kinase 70.
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Figure 3: The signaling network induced by the non-canonical CXCR4 ligands MIF, extracellular ubiquitin, and gp120. (A) MIF induces signal transduction by binding to the CXCR4, which can form a receptor complex with CD74 under certain conditions, or by binding to the atypical chemokine receptor 3 (ACKR3) (previously called CXCR7). MIF binding to CXCR4 triggers cytosolic Ca2+ influx, integrin activation, and ZAP-70 activation via Gαi, resulting in cell adhesion, migration, proliferation, and GRK2 expression. By binding to the CXCR4/CD74 signaling complex, MIF activates ERK1/2 and AKT signaling promoting cell survival and proliferation. Additionally, the MIF–CXCR4/CD74 interaction promotes JNK phosphorylation, which results in enhanced CXCL8 expression. By binding to ACKR3 MIF induces platelet survival via the activation of PI3K and AKT. (B) By binding to CXCR4, ubiquitin induces the migration of cancer as well as THP1 cells through the activation of Gαi-dependent PLC-induced Ca2+ influx, MAPK, and AKT phosphorylation. The HIV glycoprotein gp120 uses CXCR4 as co-receptor for fusion of viral and host cell membrane, which results in HIV infection. In addition, gp120 can induce cell death via CXCR4 by activating caspases, p53-dependent cytochrome C release, and PI3K/AKT-dependent Fas ligand expression. AKT, protein kinase B; Ca2+, calcium ions; Cyt. C, cytochrome C; ERK1/2, extracellular signal-regulated kinases 1/2; Gαi, Gi-protein subunit α; gp120, glycoprotein 120; GRK2, G protein-coupled receptor kinase 2; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MIF, macrophage migration inhibitory factor; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; THP1, monocytic cell line; ZAP-70, zeta-chain-associated protein kinase 70.

Mentions: CD74, the surface-expressed form of MHC class-II-associated invariant chain, has been identified as a MIF receptor. In a signaling complex with CD44, MIF/CD74 interaction leads to ERK1/2 and AKT phosphorylation promoting cell survival and proliferation (155–157) (Figure 3A). The chemotactic properties of MIF are mediated via binding to the chemokine receptors CXCR2 and CXCR4 (4), in part by interaction with CD74. Interaction of MIF with CXCR2 has been shown to mediate the recruitment and arrest of monocytes and neutrophils (4, 158), with MIF–CXCR2-induced signaling discussed in detail previously (19). Via CXCR4, MIF has been shown to recruit many cell types, including T-cells, B-cells, eosinophils, endothelial progenitor cells, mesenchymal stromal cells, as well as cancer cells (4, 148, 159–162). Furthermore, MIF–CXCR4 interaction increases in experimental bladder inflammation (163), with PAR4-induced abdominal hypersensitivity shown to occur through MIF and at least partially also through CXCR4 on the urothelium (149). However, the underlying signaling events of MIF–CXCR4 association are only partially enlightened.


Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives.

Pawig L, Klasen C, Weber C, Bernhagen J, Noels H - Front Immunol (2015)

The signaling network induced by the non-canonical CXCR4 ligands MIF, extracellular ubiquitin, and gp120. (A) MIF induces signal transduction by binding to the CXCR4, which can form a receptor complex with CD74 under certain conditions, or by binding to the atypical chemokine receptor 3 (ACKR3) (previously called CXCR7). MIF binding to CXCR4 triggers cytosolic Ca2+ influx, integrin activation, and ZAP-70 activation via Gαi, resulting in cell adhesion, migration, proliferation, and GRK2 expression. By binding to the CXCR4/CD74 signaling complex, MIF activates ERK1/2 and AKT signaling promoting cell survival and proliferation. Additionally, the MIF–CXCR4/CD74 interaction promotes JNK phosphorylation, which results in enhanced CXCL8 expression. By binding to ACKR3 MIF induces platelet survival via the activation of PI3K and AKT. (B) By binding to CXCR4, ubiquitin induces the migration of cancer as well as THP1 cells through the activation of Gαi-dependent PLC-induced Ca2+ influx, MAPK, and AKT phosphorylation. The HIV glycoprotein gp120 uses CXCR4 as co-receptor for fusion of viral and host cell membrane, which results in HIV infection. In addition, gp120 can induce cell death via CXCR4 by activating caspases, p53-dependent cytochrome C release, and PI3K/AKT-dependent Fas ligand expression. AKT, protein kinase B; Ca2+, calcium ions; Cyt. C, cytochrome C; ERK1/2, extracellular signal-regulated kinases 1/2; Gαi, Gi-protein subunit α; gp120, glycoprotein 120; GRK2, G protein-coupled receptor kinase 2; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MIF, macrophage migration inhibitory factor; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; THP1, monocytic cell line; ZAP-70, zeta-chain-associated protein kinase 70.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4543903&req=5

Figure 3: The signaling network induced by the non-canonical CXCR4 ligands MIF, extracellular ubiquitin, and gp120. (A) MIF induces signal transduction by binding to the CXCR4, which can form a receptor complex with CD74 under certain conditions, or by binding to the atypical chemokine receptor 3 (ACKR3) (previously called CXCR7). MIF binding to CXCR4 triggers cytosolic Ca2+ influx, integrin activation, and ZAP-70 activation via Gαi, resulting in cell adhesion, migration, proliferation, and GRK2 expression. By binding to the CXCR4/CD74 signaling complex, MIF activates ERK1/2 and AKT signaling promoting cell survival and proliferation. Additionally, the MIF–CXCR4/CD74 interaction promotes JNK phosphorylation, which results in enhanced CXCL8 expression. By binding to ACKR3 MIF induces platelet survival via the activation of PI3K and AKT. (B) By binding to CXCR4, ubiquitin induces the migration of cancer as well as THP1 cells through the activation of Gαi-dependent PLC-induced Ca2+ influx, MAPK, and AKT phosphorylation. The HIV glycoprotein gp120 uses CXCR4 as co-receptor for fusion of viral and host cell membrane, which results in HIV infection. In addition, gp120 can induce cell death via CXCR4 by activating caspases, p53-dependent cytochrome C release, and PI3K/AKT-dependent Fas ligand expression. AKT, protein kinase B; Ca2+, calcium ions; Cyt. C, cytochrome C; ERK1/2, extracellular signal-regulated kinases 1/2; Gαi, Gi-protein subunit α; gp120, glycoprotein 120; GRK2, G protein-coupled receptor kinase 2; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; MIF, macrophage migration inhibitory factor; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; THP1, monocytic cell line; ZAP-70, zeta-chain-associated protein kinase 70.
Mentions: CD74, the surface-expressed form of MHC class-II-associated invariant chain, has been identified as a MIF receptor. In a signaling complex with CD44, MIF/CD74 interaction leads to ERK1/2 and AKT phosphorylation promoting cell survival and proliferation (155–157) (Figure 3A). The chemotactic properties of MIF are mediated via binding to the chemokine receptors CXCR2 and CXCR4 (4), in part by interaction with CD74. Interaction of MIF with CXCR2 has been shown to mediate the recruitment and arrest of monocytes and neutrophils (4, 158), with MIF–CXCR2-induced signaling discussed in detail previously (19). Via CXCR4, MIF has been shown to recruit many cell types, including T-cells, B-cells, eosinophils, endothelial progenitor cells, mesenchymal stromal cells, as well as cancer cells (4, 148, 159–162). Furthermore, MIF–CXCR4 interaction increases in experimental bladder inflammation (163), with PAR4-induced abdominal hypersensitivity shown to occur through MIF and at least partially also through CXCR4 on the urothelium (149). However, the underlying signaling events of MIF–CXCR4 association are only partially enlightened.

Bottom Line: This has complicated the understanding of CXCR4-mediated signaling and associated biological processes.Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4.Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen University , Aachen , Germany.

ABSTRACT
CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus) and human β3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.

No MeSH data available.


Related in: MedlinePlus