CXCR4

CXCR4, or C-X-C chemokine receptor type 4, is a G protein-coupled receptor in the chemokine receptor family that binds the chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1). In humans, CXCR4 is encoded by the CXCR4 gene. The receptor mediates chemotaxis and cell survival across diverse cell types and is involved in embryonic development, hematopoiesis, and immune cell trafficking. CXCR4 often signals through Gi-type G proteins, activating downstream pathways such as MAPK/ERK, PI3K/AKT, and intracellular calcium flux, which influence cell migration, proliferation, and survival. The receptor is expressed in many tissues, with particularly important roles in bone marrow–stromal niches and lymphoid organs.

Physiologic roles include stem cell homing and retention in bone marrow; trafficking of T and B cells; neural and cardiovascular development; angiogenesis; and metastasis of cancer cells to CXCL12-rich sites.

Clinical relevance and targets: CXCR4 serves as an entry coreceptor for X4-tropic HIV-1 strains; blocking CXCR4 can inhibit viral entry in vitro, but clinical use is complicated by essential host functions. In oncology, high CXCR4 expression correlates with metastatic spread; therapies aim to disrupt CXCR4/CXCL12 signaling to limit metastasis. Plerixafor (AMD3100) is a small-molecule CXCR4 antagonist approved to mobilize hematopoietic stem cells for transplantation; other antagonists and antibodies are under investigation.

Regulation and interactions: Ligand binding triggers receptor internalization and desensitization via beta-arrestins; CXCR4 interacts with CXCR7/ACKR3, which modulates CXCL12 availability and signaling.