The Chemokine Receptor CXCR4 in Cell Proliferation and Tissue Regeneration

Abstract

The CXCR4 receptor upon binding its ligands triggers multiple signaling pathways that orchestrate cell migration, hematopoiesis and cell homing, and retention in the bone marrow. However, CXCR4 also directly controls cell proliferation of non-hematopoietic cells. This review focuses on recent reports pointing to its pivotal role in tissue regeneration and stem cell activation, and discusses the connection to the known role of CXCR4 in promoting tumor growth. The mechanisms may be similar in all cases, since regeneration often recapitulates developmental processes, and cancer often exploits developmental pathways. Moreover, cell migration and cell proliferation appear to be downstream of the same signaling pathways. A deeper understanding of the complex signaling originating from CXCR4 is needed to exploit the opportunities to repair damaged organs safely and effectively.

Keywords: CXCL12; CXCR4; HMGB1; cancer; chemokine; tissue regeneration.

FIGURE 1

Schematic representation of the signaling pathways activated by CXCR4. Ligand binding to CXCR4 activates G protein subunits and the downstream Ca²⁺ mobilization from intracellular stores and PI3K/Akt, PLC, and ERK1/2 pathways. This results in gene transcription, cell migration, proliferation and survival. CXCR4 oligomerization can also activate the G-protein independent JAK/STAT pathway. β-arrestins are recruited following GRK phosphorylation of CXR4 and mediate its internalization. ACKR3 is another receptor for CXCL12 that can induce β-arrestin-mediated signaling both by itself or as a heterodimer with CXCR4.