Upon agonistic binding to CXCR4, CXCL12 is internalized and finally subjected to lysosomal degradation. Activation of CXCR4 induces β-arrestin–mediated signaling. Based on their sequence similarity, the Gα subunits are divided into four families (Gαs, Gαi, Gαq, and Gα12) that regulate the GPCR signal via different routes. Chemokine receptors are primarily Gαi-coupled receptors and thus can be inhibited by pertussus toxin. Ligand stimulation can result in an increase in intracellular calcium. The Gαq family acts via PLC (such as PLCβ) to activate phosphatidylinositol-specific phospholipases, which hydrolyze PIP2 to generate two second messengers, IP3 and DAG. IP3 and DAG increase the intracellular free Ca2+ concentrations and activate some protein kinases, including PKC. Through PYK2, Cdc42, Rac1 and PAK, Gαq activates the transcription factor NFκB. The Gαs subunit stimulates adenyl cyclase whereas Gαi inhibits adenyl cyclase. The adenylyl cyclase activity regulates cell survival, proliferation, and chemotaxis. Although Gαi triggers PI3K/AKT/mTOR and ERK1/2, the Gβγ dimer triggers intracellular calcium mobilization through PLC. PI3K can activate AKT, which has been found to play a key role in tumor cell survival and proliferation. However AKT may not be the only player in cell survival signaling. Both p38 (not shown) and ERK1/2 have been implicated in tumor cell survival. CXCL12 can promote cell survival through inactivation of the proapoptotic Bcl-2 antagonist of cell death (BAD) protein. Thus, CXCL12 may promote cell survival by two mechanisms: post-translational inactivation of the cell death machinery and an increased transcription of cell survival-related genes.Lymphocyte trafficking, one of the major functions of chemokines, is mediated by PI3 kinase, which ca be activated by Gβγ and Gα subunits. PI3K activation can result in the phosphorylation of various focal adhesion components (e.g. proline-rich kinase-2 (Pyk-2), Crk, Crk-associated substrate, focal adhesion kinase (FAK), paxillin). Crk, which belongs to the adaptor family of proteins composed of SH2 and SH3 domains, has a putative role in signaling. Thus, chemotaxis has been shown to be mediated via MAPK either through PKC, or through Gαi, which can signal through Erk/1/2 (14, 19). CXCR4 signaling has been shown to involve the Ras-activated signaling pathway, several src-related kinases such as Src, Lyn, Fyn, and Lck, T-cell activating molecule ZAP-70, and vav and small GTPases.
Note: CXCL12 not only acts on CXCR4, but can also bind to CXCR7 that CXCR4 can form heterodimers with CXCR4.