CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer

Abstract

Chemokines are a group of about 50 chemotactic cytokines crucial for the migration of immune system cells and tumor cells, as well as for metastasis. One of the 20 chemokine receptors identified to date is CXCR2, a G-protein-coupled receptor (GPCR) whose most known ligands are CXCL8 (IL-8) and CXCL1 (GRO-α). In this article we present a comprehensive review of literature concerning the role of CXCR2 in cancer. We start with regulation of its expression at the transcriptional level and how this regulation involves microRNAs. We show the mechanism of CXCR2 signal transduction, in particular the action of heterotrimeric G proteins, phosphorylation, internalization, intracellular trafficking, sequestration, recycling, and degradation of CXCR2. We discuss in detail the mechanism of the effects of activated CXCR2 on the actin cytoskeleton. Finally, we describe the involvement of CXCR2 in cancer. We focused on the importance of CXCR2 in tumor processes such as proliferation, migration, and invasion of tumor cells as well as the effects of CXCR2 activation on angiogenesis, lymphangiogenesis, and cellular senescence. We also discuss the importance of CXCR2 in cell recruitment to the tumor niche including tumor-associated neutrophils (TAN), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and regulatory T (T_reg) cells.

Keywords: CXCL1; CXCR2; GRO-α; MGSA; cancer; chemokine; interleukin-8; migration.

Figure 1

Regulation of CXCR2 by miRNAs. CXCR2 expression is regulated by miRNAs. Diseases such as cancer, ischemic stroke, atrial fibrillation, and neuropathic pain are associated with a decrease in the level of some miRNAs which results in a pathological increase in CXCR2 expression. Fungus Cordyceps militaris contains miRNAs that decrease the expression of CXCR2. The increased expression of CXCR2 can be physiological—it is often related to a decrease in the levels of certain miRNAs, resulting in an increase in CXCR2 expression and thus normal cell and tissue function. This is exemplified by osteoclast precursors, where increased CXCR2 expression leads to the differentiation of these cells into osteoclasts. This mechanism has been observed in root resorption associated with orthodontic tooth movement. Furthermore, increased CXCR2 expression on endothelial cells increases their proliferation which is associated with the preservation of endothelial integrity. CXCR2 activity is the effect of miRNAs on GRK2 expression. This mechanism is significant in cell infection by KSHV.

Figure 2

Consequences of G-protein activation by CXCR2. CXCR2 belongs to the seven transmembrane G-protein-coupled receptor family. CXCR2 is coupled with Gα_i—upon CXCR2 activation, this G protein dissociates into heterodimer of Gβγ and Gα_i subunits. Gα_i subunit inhibits adenylyl cyclase activity, while Gβγ activates PI3K and PLC-β. Activation of PLC-β results in the production of DAG and IP₃. IP₃ induces the mobilization of Ca²⁺.

Figure 3

Importance of phosphorylation in the function of CXCR2 receptor. As a consequence of activation by its ligand, CXCR2 is phosphorylated at the C-terminus by GRK2 and GRK6. This leads to desensitization and subsequent internalization of CXCR2. In endosomes CXCR2 is dephosphorylated by PP2A, which leads to its resensitization and being recycled back to the cell membrane.

Figure 4

CXCR2 as a chemosynapse. Activated and inactivated CXCR2 bind various proteins which play an important role in signal transduction from this receptor. One such is NHERF1, which localizes PLC-β close to CXCR2—this allows the receptor to efficiently activate PLC-β. The activation of CXCR1 is followed by the dissociation of gelsolin and plastin, proteins which regulate the formation of F-actin close to the activated CXCR2 receptor. Moreover, upon CXCR2 activation, F-actin begins to bind to CXCR2 via VASP and IQGAP1—these processes lead to cell migration as a consequence of CXCR2 activation. Furthermore, CXCR2 activation mediated by LASP-1 is followed by the activation of various proteins including Cdc42, ERK MAPK, p130^CAS, and Src.

Figure 5

CXCR2 trafficking. Upon activation, CXCR2 is phosphorylated, and Hip and AP2 attach to the LLKIL motif at the C-terminus, which is also ubiquitinated. Clathrin and β-arrestin bind to AP2, resulting in the formation of a clathrin-coated pit. As a result, CXCR2 undergoes Rab5-dependent internalization into early endosomes. Subsequently, CXCR2 undergoes RhoB-dependent sorting decisions. CXCR2 can transition to recycling endosomes depending on Rab11a and then is transported back into the cell membrane. CXCR2 can also move to late endosomes and eventually to lysosomes in a Rab7-dependent process, which leads to the degradation of CXCR2.