Limits...
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

CXCL12-induced signaling pathways. CXCL12 can trigger intracellular signaling by binding to CXCR4 monomers, CXCR4 homodimers, ACKR3, or CXCR4/ACKR3 heterodimers. CXCR4 preferentially activates G protein-mediated signaling, which is negatively regulated by RGS16. The atypical chemokine receptor ACKR3 (previously called CXCR7) functions as a CXCL12 scavenger and also signals via β-arrestin. Also, complex formation between CXCR4 and ACKR3 shifts CXCL12-induced signaling away from classical G protein signaling to β-arrestin signaling. By CXCL12-induced dimerization, CXCR4 has also been reported to induce JAK/STAT signaling. Whereas CXCR4 is mostly degraded after CXCL12-elicited internalization, ACKR3 is continuously internalized and recycled to plasma membrane independent of ligand binding, a process that also promotes CXCL12 degradation. CXCL12 is known to induce chemotaxis and proliferation, supporting several downstream biological processes such as hematopoietic development, angiogenesis, or tumor progression. AKT, protein kinase B; Ca2+, calcium ions; Gα, G protein subunit α; Gβγ, G protein subunit βγ; JAK, janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; RGS16, regulator of G protein signaling 16; STAT, signal transducer and activator of transcription.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4543903&req=5

Figure 2: CXCL12-induced signaling pathways. CXCL12 can trigger intracellular signaling by binding to CXCR4 monomers, CXCR4 homodimers, ACKR3, or CXCR4/ACKR3 heterodimers. CXCR4 preferentially activates G protein-mediated signaling, which is negatively regulated by RGS16. The atypical chemokine receptor ACKR3 (previously called CXCR7) functions as a CXCL12 scavenger and also signals via β-arrestin. Also, complex formation between CXCR4 and ACKR3 shifts CXCL12-induced signaling away from classical G protein signaling to β-arrestin signaling. By CXCL12-induced dimerization, CXCR4 has also been reported to induce JAK/STAT signaling. Whereas CXCR4 is mostly degraded after CXCL12-elicited internalization, ACKR3 is continuously internalized and recycled to plasma membrane independent of ligand binding, a process that also promotes CXCL12 degradation. CXCL12 is known to induce chemotaxis and proliferation, supporting several downstream biological processes such as hematopoietic development, angiogenesis, or tumor progression. AKT, protein kinase B; Ca2+, calcium ions; Gα, G protein subunit α; Gβγ, G protein subunit βγ; JAK, janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; RGS16, regulator of G protein signaling 16; STAT, signal transducer and activator of transcription.

Mentions: CXCR4 is classified as a GPCR, indicating that one of the main pathways triggered by CXCR4 stimulation involves G protein-coupled signaling (Figure 2). The G protein complex is a heterotrimeric complex, composed of a Gα, Gβ, and Gγ subunit (Box 4), and is associated with CXCR4 and the inner leaflet of the plasma membrane. CXCR4 is mainly coupled to the Gαi subunit, which after dissociation of the Gαβγ complex upon CXCR4 stimulation, inhibits adenylyl cyclase activity, and triggers mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathway activation (96). The Gβγ subunit leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) by phospholipase C (PLC) and subsequent mobilization of Ca2+ ions from intracellular stores (103, 104). This could also be considered a downstream effect of Gαi activity, since the inhibition of Gαi activity by its potent inhibitor pertussis toxin has been reported to lead to decreased Ca2+ mobilization from intracellular stores (103, 105). Although CXCR4 is most likely primarily coupled to Gαi, recent reports suggest that CXCR4 associates with other Gα subunits, i.e., Gαq or Gα12, each of which has been associated with different intracellular signaling cascades (Box 4) (106).


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)

CXCL12-induced signaling pathways. CXCL12 can trigger intracellular signaling by binding to CXCR4 monomers, CXCR4 homodimers, ACKR3, or CXCR4/ACKR3 heterodimers. CXCR4 preferentially activates G protein-mediated signaling, which is negatively regulated by RGS16. The atypical chemokine receptor ACKR3 (previously called CXCR7) functions as a CXCL12 scavenger and also signals via β-arrestin. Also, complex formation between CXCR4 and ACKR3 shifts CXCL12-induced signaling away from classical G protein signaling to β-arrestin signaling. By CXCL12-induced dimerization, CXCR4 has also been reported to induce JAK/STAT signaling. Whereas CXCR4 is mostly degraded after CXCL12-elicited internalization, ACKR3 is continuously internalized and recycled to plasma membrane independent of ligand binding, a process that also promotes CXCL12 degradation. CXCL12 is known to induce chemotaxis and proliferation, supporting several downstream biological processes such as hematopoietic development, angiogenesis, or tumor progression. AKT, protein kinase B; Ca2+, calcium ions; Gα, G protein subunit α; Gβγ, G protein subunit βγ; JAK, janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; RGS16, regulator of G protein signaling 16; STAT, signal transducer and activator of transcription.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: CXCL12-induced signaling pathways. CXCL12 can trigger intracellular signaling by binding to CXCR4 monomers, CXCR4 homodimers, ACKR3, or CXCR4/ACKR3 heterodimers. CXCR4 preferentially activates G protein-mediated signaling, which is negatively regulated by RGS16. The atypical chemokine receptor ACKR3 (previously called CXCR7) functions as a CXCL12 scavenger and also signals via β-arrestin. Also, complex formation between CXCR4 and ACKR3 shifts CXCL12-induced signaling away from classical G protein signaling to β-arrestin signaling. By CXCL12-induced dimerization, CXCR4 has also been reported to induce JAK/STAT signaling. Whereas CXCR4 is mostly degraded after CXCL12-elicited internalization, ACKR3 is continuously internalized and recycled to plasma membrane independent of ligand binding, a process that also promotes CXCL12 degradation. CXCL12 is known to induce chemotaxis and proliferation, supporting several downstream biological processes such as hematopoietic development, angiogenesis, or tumor progression. AKT, protein kinase B; Ca2+, calcium ions; Gα, G protein subunit α; Gβγ, G protein subunit βγ; JAK, janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositide 3-kinase; PLC, phospholipase C; RGS16, regulator of G protein signaling 16; STAT, signal transducer and activator of transcription.
Mentions: CXCR4 is classified as a GPCR, indicating that one of the main pathways triggered by CXCR4 stimulation involves G protein-coupled signaling (Figure 2). The G protein complex is a heterotrimeric complex, composed of a Gα, Gβ, and Gγ subunit (Box 4), and is associated with CXCR4 and the inner leaflet of the plasma membrane. CXCR4 is mainly coupled to the Gαi subunit, which after dissociation of the Gαβγ complex upon CXCR4 stimulation, inhibits adenylyl cyclase activity, and triggers mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathway activation (96). The Gβγ subunit leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) by phospholipase C (PLC) and subsequent mobilization of Ca2+ ions from intracellular stores (103, 104). This could also be considered a downstream effect of Gαi activity, since the inhibition of Gαi activity by its potent inhibitor pertussis toxin has been reported to lead to decreased Ca2+ mobilization from intracellular stores (103, 105). Although CXCR4 is most likely primarily coupled to Gαi, recent reports suggest that CXCR4 associates with other Gα subunits, i.e., Gαq or Gα12, each of which has been associated with different intracellular signaling cascades (Box 4) (106).

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