The CXCL12/CXCR4/ACKR3 Signaling Axis Regulates PKM2 and Glycolysis

Abstract

In response to CXCL12, CXCR4 and ACKR3 both recruit β-arrestin 2, regulating the assembly of interacting proteins that drive signaling and contribute to the functions of both receptors in cancer and multiple other diseases. A prior proteomics study revealed that β-arrestin 2 scaffolds pyruvate kinase M2 (PKM2), an enzyme implicated in shifting cells to glycolytic metabolism and poor prognosis in cancer. We hypothesized that CXCL12 signaling regulates PKM2 protein interactions, oligomerization, and glucose metabolism. We used luciferase complementation in cell-based assays and a tumor xenograft model of breast cancer in NSG mice to quantify how CXCR4 and ACKR3 change protein interactions in the β-arrestin-ERK-PKM2 pathway. We also used mass spectrometry to analyze the effects of CXCL12 on glucose metabolism. CXCL12 signaling through CXCR4 and ACKR3 stimulated protein interactions among β-arrestin 2, PKM2, ERK2, and each receptor, leading to the dissociation of PKM2 from β-arrestin 2. The activation of both receptors reduced the oligomerization of PKM2, reflecting a shift from tetramers to dimers or monomers with low enzymatic activity. Mass spectrometry with isotopically labeled glucose showed that CXCL12 signaling increased intermediate metabolites in glycolysis and the pentose phosphate pathway, with ACKR3 mediating greater effects. These data establish how CXCL12 signaling regulates PKM2 and reprograms cellular metabolism.

Analysis of C-X-C motif chemokine receptors in breast cancer: potential value in immunotherapy and prognostic prediction

“…Specifically, the binding of CXCR4 to its ligand triggers the recruitment of β-arrestin molecules, which then initiates β-arrestin-dependent signaling through the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Meanwhile, phosphorylated ERK1/2 drives pyruvate kinase M2 (PKM2) to upregulate glycolytic genes, triggering the pentose phosphate pathway and promoting glucose metabolism to a greater extent reshaping the metabolic reprogramming of cancer cells ( 49 ). Furthermore, by comparing the characteristics of 22 infiltrating immune cells in subgroups A and B, we found that the poor prognostic factors in subgroup A were closely associated with M2 polarization.…”

Cancer-associated fibroblasts: challenges and opportunities

“…The following provides two examples. CXCL12 secreted by CAFs signals through receptors CXCR4 and/or ACKR3 to drive numerous processes required for tumor growth and metastasis, including proliferation, glycolytic metabolism, and migration/invasion [ 23 – 28 ]. CAFs secrete various isoforms of CXCL12 with CXCL12-γ, an isoform with high binding affinity to heparan sulfate proteoglycan extracellular matrix molecules, producing greatest effects to drive metastasis [ 29 ].…”