Regulation of CXCR4 signaling

Abstract

The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoiesis, and immune response. Recent evidence has highlighted the role of CXCR4 in a variety of diseases including HIV, cancer, and WHIM syndrome. Importantly, the involvement of CXCR4 in cancer metastasis and WHIM syndrome appears to be due to dysregulation of the receptor leading to enhanced signaling. Herein we review what is currently known regarding the regulation of CXCR4 and how dysregulation contributes to disease progression.

Figure 1. Signal Transduction Pathways and Regulation of CXCR4

SDF binding to CXCR4 leads to the activation of multiple G protein-dependent signaling pathways, resulting in diverse biological outcomes such as migration, adhesion, and transcriptional activation. Pathways activated and outcomes elicited may differ between CXCR4⁺ cell types. Two potential G protein-independent pathways have been described. Tyrosine phosphorylation of CXCR4 results in the recruitment and activation of the JAK/STAT pathway, while p38 and ERK activation has been shown to be partially dependent on arrestin-3. Following activation, GRK phosphorylation results in the recruitment of arrestin 2/3 and subsequent internalization. CXCR4 is also ubiquitinated by AIP4 at the plasma membrane, which results in its sorting to and degradation in lysosomes. However, a portion of the internalized receptor may also recycle back to the plasma membrane.

Figure 2. Amino Acid Sequence of the C-terminal Tail of CXCR4

A) The C-terminal tail of CXCR4 contains 15 serine and 3 threonine residues. Truncation and alanine scanning mutagenesis has identified multiple residues as potential phospho-acceptor sites (highlighted in yellow) as well as those residues important for degradation (highlighted in red). Evidence to date suggests that multiple GRKs are responsible for homologous desensitization of CXCR4. Additionally, multiple residues are potential PKC phosphorylation sites. B) Amino acid sequence of CXCR4 as a result of the various germline mutations identified to date resulting in WHIM syndrome.