Figure 1. CXCR signaling pathway.
Overview of CXCR
It is well known that inappropriate regulation of chemokines or chemokine receptors is a major potential pathogenic factor in chronic inflammation and many autoimmune diseases. They can act directly or indirectly on tumor cells or other cells, thereby affecting tumor progression. About 50 chemokines and 20 related receptors are now known. Chemokine receptors are a class of GTP-protein-coupled transmembrane receptors (GPCRs) that mediate the function of chemokines and are normally expressed on cell membranes such as immune cells and endothelial cells. They are G-protein coupled receptors with 7 transmembrane structures, which are mainly transduced by G proteins, with certain subfamily specificity for binding to receptors. Chemokine receptors can be divided into four subfamilies: CXC receptors (CXCR), CC receptors (CCR), class C receptors (XCR), and CX3C receptors (CX3CR). There are currently 7 known CXCR chemokine receptors, 10 single CC receptor ligands (CCL), C receptor ligands (XCL1/2) and CX3C receptor ligands (CX3CL1). Despite the high selectivity for binding to subfamily chemokine receptors and ligands, most chemokine receptors still exhibit great hybridity when interacting with ligands of the same subfamily.
The CXCR signaling pathway family mainly comprises chemokines and chemokine receptors and CXCR consists of about 330 amino acids. The seven transmembrane regions divide the molecule into an extracellular free N-terminus, three extracellular loops, three intracellular loops, and several C-terminal portions. The intracellular second loop is a site that is coupled to a heterotrimeric G-protein and has a characteristic aspartate-arginine-tyrosine box amino acid sequence. The alpha subunit of the heterotrimeric G-protein coupled to the chemokine receptor is Gi/o and is sensitive to pertussis toxin. Chemokines are small types of secreted proteins that are capable of directional migration of chemotactic cells and consist of 70 to 100 amino acids. More than 40 human chemokines have been discovered to date, belonging to the largest family of cytokines. When tissue cells and immune cells such as fibroblasts, endothelial cells, and epidermal cells are induced by stimuli such as growth factors, interferons, viral products, and bacterial products, different chemokines can be secreted. There are four conserved cysteines (C) in the molecule of the chemokine. According to whether other amino acids are inserted between the first two Cs near the amino terminus (N-terminus) of the molecule, they are divided into four subclasses: CXC (insert 1 amino acid residue), also known as α-chemokine, such as IL-8 (Interleukin-8); CC (without insertion of other amino acid residues), also known as beta-chemokines, such as MCP-1 (Monocyte chemoattractant protein-1); CX3C (insert 3 other amino acids) such as fractalkine; class C (only one C at the N end), such as lymphotactin. The chemokines currently found mainly belong to the alpha and beta classes. In the molecular structure, they are folded into free by disulfide bonds.
CXCR signaling pathway
CXCR signaling pathway cascade
The conduction of the CXCR signaling pathway requires the combination of chemokines and the corresponding CXCR to initiate downstream responses. The CXCR signaling pathway mainly mediates the following effects. We will introduce the cascade through the role of CXCR in different effects: many facts prove that Chemokines regulate the proliferation of tumor cells in epithelial tissues and blood. Most tumor cells themselves produce chemokines and maintain cell proliferation through autocrine or paracrine expression. In many cases, chemokines and their receptors can affect mutations in proto-oncogenes. These activated oncogenes can directly up- or down-regulate a specific set of chemokines and their receptors as part of the initiation of a carcinogenic process. It is well known that activation of chemokine receptors in tumor cells can trigger the production of many intracellular signals that cause cell proliferation. In addition to the above-mentioned chemokines and their receptors directly promoting cell proliferation, tumor cell growth can also be indirectly regulated by the epidermal growth factor receptor (EGFR). Atypical chemokine receptor 3 (ACKR3) in breast and prostate cancer cells was originally identified as a "bait" receptor that targets the degradation of CXCL12 and CXCL11. In prostate and breast cancer cells, ACKR3 up-regulates EGFR expression and phosphorylation by relying on the physical binding of β-arrestin to EGFR, and their interaction is independent of any agonist. This activity of ACKR3 has been shown to be associated with other cancers, for example, to affect the progression of kidney and lung cancer patients. In addition, high expression of ACKR1, ACKR2, and ACKR4 can affect the prognosis of cervical squamous cell carcinoma and gastric cancer and prolong the survival time of patients. Chemokines and their receptors not only promote the proliferation of tumor cells but also inhibit the growth of tumor cells. There is evidence that, in some cases, chemokines are capable of inducing apoptosis in tumor cells, depending on the activity of specific proteins of tumor suppressor or pathogenic genes. Tumor suppressor can protect cells from tumor invasion by inhibiting the cell cycle or the like. Human tumor suppressor gene 53 (TP53)-mediated upregulation of CX3CL1 may be a tumor suppressor mechanism of acellular autoimmunity, while down-regulation of CXCR4 may inhibit proliferation and migration of breast cancer cells. Therefore, down-regulation of CXCR4 may be a branch of cellular autorepression shared by various tumor suppressor genes. Chemokines and their receptors also modulate the activity of tumor suppressor genes. TP53 with unmutated CCR5 is initially observed in breast cancer cell lines, and siRNA is activated by CCL5 to activate TP53 through JAK2 and p38 - MAPK signaling pathways. Therefore, CCL5 stimulation can lead to CCR5-dependent upregulation of TP53 transcription targeting. It is well known that aging is a process that inhibits cells from re-entering the cell cycle, leading to irreversible growth arrest. Aging cells are still metabolically active, producing and secreting certain complex mixtures including proteases, growth factors, cytokines, and chemokines. These mixtures can regulate the activation of TP53 through a CXCR2-dependent mechanism, thereby accelerating the aging process. In addition, TP53 also regulates the up-regulation of CXCR2, suggesting that CXCR2 ligand activates TP53 transcriptional activity, which in turn activates the CXCR2 promoter to accelerate cellular senescence. Cells can avoid programmed cell death through apoptosis. This molecular clue is the key to the progression of malignant tumors to highly resistant malignancies. Chemokine receptors mediate the activation of the PI3K/AKT/NF-κB pathway, which up-regulates the expression of Bcl2 and its associated proteins, as well as down-regulates Bax, and the expression of Bak protein, a protein that promotes apoptosis, mainly by inhibiting the balance between protein precursors and inhibitory proteins. Studies have found that the use of specific CCL2 inhibitors can delay lung cancer progression in these mice, suggesting that the interaction between CCR5/NF-κB/CCL2 is critical during tumor progression. Activation of the ERK pathway also activates the pro-active activity of chemokine receptors. Activation of the ERK pathway regulates the prodrug activity of CCR3, CCR8 and CCR7 in lymphoma and non-small cell lung cancer cells by inducing phosphorylation of pro-apoptotic proteins and inactivating activated surviving proteins. In addition, a large amount of data indicates that chemokines and their receptors can also inhibit tumor cell apoptosis by regulating autophagy. Chemokines and their receptors regulate a variety of biological functions including inflammatory responses. Chemokines and their receptors can transport inflammatory cells into tissues and organs, which makes them play a key role in the process of tumor immune infiltration. The expression of specific chemokines is associated with the transformation of oncogenes and tumor suppressor genes. It is well known that TP53 is a negative regulator of NF-κB, and NF-κB is a key transcription factor that promotes the formation of an immunosuppressive environment. More and more studies have shown that immune infiltration is not only important in the early stages of carcinogenesis, but also determines the progression of malignant tumors. There is still considerable cross-over between chemokine receptors expressed on effector cells and immunosuppressive cells, which may explain the dual activities of most chemokines in regulating tumor immune processes, CCR7 and its ligand CCL19.
Due to the complexity and importance of the CXCR signaling pathway, many protein factors or signaling pathways can regulate the CXCR signaling pathway. Here are a few obvious modes of regulation: Wnt signaling pathway is the key signaling pathway that determines cell fate during embryonic development and tissue formation. It encodes and secretes a variety of cytokines, and affects the proliferation, polarization, differentiation, aging and apoptosis of cells during embryonic and tissue development. It plays a vital role in the development of kidney and glomeruli. The classical Wnt signaling pathway is involved in regulation pancreas development, regulation of pancreatic β-cell proliferation and insulin function, mutations or abnormalities can cause a variety of renal lesions including fibrosis, diabetic nephropathy. Studies have shown that Wnt ligands can activate the canonical Wnt signaling pathway in vitro, and the DKK family can inhibit the classical Wnt signaling pathway. It is one of the hotspots of medical research in recent years to promote the targeted homing of stem cells by up-regulating the expression of CXCR4 on the surface of stem cells, thereby promoting the therapeutic effect of stem cells and improving the therapeutic effect after stem cell transplantation. The classical Wnt signaling pathway regulates the transformation and differentiation of stem cells, and it has been confirmed that the classical Wnt signaling pathway is involved in the regulation of the migration of BMSCs to the extracellular matrix. However, the exact mechanism and effects still remain controversial. Many studies have found that miR155 has a significant differential expression in PE placenta, especially in severe PE placenta. Studies have also shown that in gastric cancer, breast cancer, and other diseases, miR155 can target the regulation of CXCR4 expression, affect cancer cell proliferation and angiogenesis, and increase the invasiveness of tumor cells. Therefore, miR155 may inhibit the phosphorylation of downstream AKT protein by inhibiting the expression of CXCR4 in trophoblasts, affecting the activation of the PI3K/AKT pathway, and reducing the invasion and migration of trophoblasts. The SDF-1/CXCR4 pathway plays an important role in endothelial formation, angiogenesis, and hematopoiesis. Studies have shown that SDF-1 can promote the expression of VEGF on endothelial cells and is an important cytokine for mobilizing EPCs. SDF-1 is a CD34+ hematopoietic progenitor chemokine that mediates the migration of hematopoietic progenitor cells and plays an important role in the homing of progenitor cells to the bone marrow. Studies in SDF-1 knockout mice have shown that SDF-1/CXCR4 plays an important role in cardiovascular production. SDF-1/CXCR4 can trigger a variety of signal transduction pathways in the body, including PI3K/Akt, NF-κB, MAPKs and Ca2+ influx, which are thought to be closely related to cell proliferation and apoptosis.
Relationship with diseases
It has been confirmed that there are excessive expressions in different cancers, including liver cancer and breast cancer. The corresponding in vivo and in vitro experiments have proved that the inhibition of CXCR expression can effectively inhibit the occurrence and amplification of cancer.
The expression levels of CXCR1 and IL-8 in peripheral blood mononuclear cells of patients with chronic hepatitis B are significantly increased. After interferon treatment, the expression level of CXCR1 and IL-8 is down-regulated, which may be related to the mechanism of chronic hepatitis B inflammation.
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Zhang B, Liu N, Gu B, et al. Effect of high glucose on migration of BMSCs through inhibiting CXCR-4. Shanghai Journal of Stomatology. 2014, 23(6):646.
Zou J, Redmond A K, Qi Z, et al. The CXC chemokine receptors of fish: Insights into CXCR evolution in the vertebrates. General & Comparative Endocrinology. 2015, 215:117-131.
Ferrer-Marin F, Gutti R, Liu Z J, et al. MiR‐9 contributes to the developmental differences in CXCR‐4 expression in human megakaryocytes. Journal of Thrombosis & Haemostasis. 2014, 12(2):282-285.
Zamarchi R, Allavena P, Borsetti A, et al. Expression and functional activity of CXCR-4 and CCR-5 chemokine receptors in human thymocytes. Clinical & Experimental Immunology. 2002, 127(2):321–330.
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