Figure 1.

CXCL12-CXCR4/CXCR7 signaling pathway. CXCL12 is widely expressed in various tissues, such as liver, brain, lung, kidney, heart, spleen and bone marrow. Upon CXCL12 binding to CXCR4, the G protein is dissociated into Gα and Gβγ subunits, which interacts with their downstream target proteins and regulates downstream signaling pathways, respectively. The Gβγ subunit activates PLC, which results in the conversion of PIP2 to DAG and IP3 and the release of Ca²⁺, followed by PKC activation and phosphorylation of target proteins. Gαi and Gβγ subunits activate PI3K-AKt pathway. Subsequent AKt activation regulates gene expression via the NF-қB pathway. Activated AKt also resulted in GSK-3 inactivation and β-Catenin stabilization. Stable β-Catenin enters the nucleus and activates gene transcription, thereby promoting cell proliferation. AKt activation also affects cell proliferation and survival by phosphorylation of inactivated B-cell lymphoma-associated cell death agonists. In addition, the Gαi subunit induces Ras protein kinase activation, which is subsequently transduced by MAPK signaling, including phosphorylation of ERK1/2. The Gαi subunit also inhibits cAMP production, thereby activating downstream pathways. Moreover, the binding of CXCL12 to CXCR4 activates the JAK/STAT pathway independent of the G protein. CXCL12 also mediates CXCR4 receptor internalization through GRK-dependent phosphorylation and subsequent interaction of CXCR4 with β-arrestin. Upon CXCL12 binding to CXCR7, no classical GPCR-mediated signaling is observed, instead signaling preferentially through β-arrestin proteins.