CXCL1

Last updated
CXCL1
Protein CXCL1 PDB 1mgs.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CXCL1 , FSP, GRO1, GROa, MGSA, MGSA-a, NAP-3, SCYB1, C-X-C motif chemokine ligand 1
External IDs OMIM: 155730; MGI: 1340094; HomoloGene: 136748; GeneCards: CXCL1; OMA:CXCL1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2919

20310

Ensembl

ENSG00000163739

ENSMUSG00000058427

UniProt

P09341

P10889

RefSeq (mRNA)

NM_001511

NM_009140

RefSeq (protein)

NP_001502

NP_033166

Location (UCSC) Chr 4: 73.87 – 73.87 Mb Chr 5: 91.05 – 91.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils [5] [6] or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. [7] This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E (normal rat kidney-52E) cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). [8] In humans, this protein is encoded by the gene CXCL1 [9] and is located on human chromosome 4 among genes for other CXC chemokines. [10]

Contents

Structure and expression

CXCL1 exists as both monomer and dimer and both forms are able to bind chemokine receptor CXCR2. [11] However, CXCL1 chemokine is able to dimerize only at higher (micromolar) concentrations and its concentrations are only nanomolar or picomolar upon normal conditions, which means that the form of WT CXCL1 is more likely monomeric while dimeric CXCL1 is present only during infection or injury. CXCL1 monomer consists of three antiparallel β-strands followed by C- terminal α-helix and this α-helix together with the first β-strand are involved in forming a dimeric globular structure. [12]

Upon normal conditions, CXCL1 is not expressed constitutively. It's produced by a variety of immune cells such as macrophages, neutrophils and epithelial cells, [13] [14] or Th17 population. Moreover, its expression can be also induced indirectly by IL-1, TNF-α or IL-17 produced again by Th17 cells [15] and is triggered mainly by activation of NF-κB or C/EBPβ signaling pathways predominantly involved in inflammation and leading to production of other inflammatory cytokines. [15]

Function

CXCL1 has a potentially similar role as interleukin-8 (IL-8/CXCL8). After binding to its receptor CXCR2, CXCL1 activates phosphatidylinositol-4,5-bisphosphate 3-kinase-γ (PI3Kγ)/Akt, MAP kinases such as ERK1/ERK2 or phospholipase-β (PLCβ) signaling pathways. CXCL1 is expressed at higher levels during inflammatory responses thus contributing to the process of inflammation. [16] CXCL1 is also involved in the processes of wound healing and tumorigenesis. [17] [18] [19]

Role in cancer

CXCL1 has a role in angiogenesis and arteriogenesis [20] and thus has been shown to act in the process of tumor progression. The role of CXCL1 was described by several studies in the development of various tumors, such as breast cancer, gastric and colorectal carcinoma or lung cancer. [21] [22] [23] Also, CXCL1 is secreted by human melanoma cells, has mitogenic properties and is implicated in melanoma pathogenesis. [24] [25] [26]

Role in nervous system and sensitization

CXCL1 plays a role in spinal cord development by inhibiting the migration of oligodendrocyte precursors. [11] CXCR2 receptor for CXCL1 is expressed in the brain and spinal cord by neurons and oligodendrocytes and during CNS pathologies such as Alzheimer's disease, multiple sclerosis and brain injury also by microglia. An initial study in mice showed evidence that CXCL1 decreased the severity of multiple sclerosis and may offer a neuro-protective function. [27] On the other hand, on the periphery, CXCL1 contributes to the release of prostaglandins and thus causes increased sensitivity to pain and drives nociceptive sensitization via recruitment of neutrophils to the tissue. Phosphorylation of ERK1/ERK2 kinases and activation of NMDA receptors leads to transcription of genes inducing chronic pain, such as c-Fos or cyclooxygenase-2 (COX-2). [16]

Related Research Articles

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in humans

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<span class="mw-page-title-main">Macrophage inflammatory protein</span> Protein family

Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β, renamed CCL3 and CCL4 respectively, since 2000. However, other names are sometimes encountered in older literature, such as LD78α, AT 464.1 and GOS19-1 for human CCL3 and AT 744, Act-2, LAG-1, HC21 and G-26 for human CCL4. Other macrophage inflammatory proteins include MIP-2, MIP-3 and MIP-5.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.

<span class="mw-page-title-main">CXCL9</span> Mammalian protein found in Homo sapiens

Chemokine ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.

<span class="mw-page-title-main">CXCL2</span> Mammalian protein found in Homo sapiens

Chemokine ligand 2 (CXCL2) is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha (MIP2-alpha), Growth-regulated protein beta (Gro-beta) and Gro oncogene-2 (Gro-2). CXCL2 is 90% identical in amino acid sequence as a related chemokine, CXCL1. This chemokine is secreted by monocytes and macrophages and is chemotactic for polymorphonuclear leukocytes and hematopoietic stem cells. The gene for CXCL2 is located on human chromosome 4 in a cluster of other CXC chemokines. CXCL2 mobilizes cells by interacting with a cell surface chemokine receptor called CXCR2.

<span class="mw-page-title-main">CXCL3</span> Mammalian protein found in Homo sapiens

Chemokine ligand 3 (CXCL3) is a small cytokine belonging to the CXC chemokine family that is also known as GRO3 oncogene (GRO3), GRO protein gamma (GROg) and macrophage inflammatory protein-2-beta (MIP2b). CXCL3 controls migration and adhesion of monocytes and mediates its effects on its target cell by interacting with a cell surface chemokine receptor called CXCR2. More recently, it has been shown that Cxcl3 regulates cell autonomously the migration of the precursors of cerebellar granule neurons toward the internal layers of cerebellum, during the morphogenesis of cerebellum. Moreover, if the expression of Cxcl3 is reduced in cerebellar granule neuron precursors, this highly enhances the frequency of the medulloblastoma, the tumor of cerebellum. In fact, the reduced expression of Cxcl3 forces the cerebellar granule neuron precursors to remain at the surface of the cerebellum, where they highly proliferate under the stimulus of Sonic hedgehog, becoming target of transforming insults. Remarkably, the treatment with CXCL3 completely prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma. Thus, CXCL3 is a target for medulloblastoma therapy. Cxcl3 is directly regulated transcriptionally by BTG2

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

<span class="mw-page-title-main">CXCL14</span> Mammalian protein found in Homo sapiens

Chemokine ligand 14 (CXCL14) is a small cytokine belonging to the CXC chemokine family that is also known as BRAK. Mature CXCL14 has many of the conserved features of the CXC chemokine subfamily but has some differences too, such as a shorter N-terminus and five extra amino acids in the region between its third and fourth cysteines. CXCL14 is constitutively expressed at high levels in many normal tissues, where its cellular source is thought to be fibroblasts. However, it is reduced or absent from most cancer cells. This chemokine is chemotactic for monocytes and can activate these cells in the presence of an inflammatory mediator called prostaglandin-E2 (PGE2). It is also a potent chemoattractant and activator of dendritic cells, is implicated in homing of these cells, and can stimulate the migration of activated NK cells. CXCL14 also inhibits angiogenesis, possibly as a result of its ability to block endothelial cell chemotaxis. The gene for CXCL14 contains four exons and is located on chromosome 5 in humans.

CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently six known CXC chemokine receptors in mammals, named CXCR1 through CXCR6.

<span class="mw-page-title-main">CXCL6</span> Mammalian protein found in Homo sapiens

Chemokine ligand 6 (CXCL6) is a small cytokine belonging to the CXC chemokine family that is also known as granulocyte chemotactic protein 2 (GCP-2). As its former name suggests, CXCL6 is a chemoattractant for neutrophilic granulocytes. It elicits its chemotactic effects by interacting with the chemokine receptors CXCR1 and CXCR2. The gene for CXCL6 is located on human chromosome 4 in a cluster with other CXC chemokine genes.

Chemokine ligand 17 (CXCL17) is a small cytokine belonging to the CXC chemokine family that has been identified in humans and mice. CXCL17 attracts dendritic cells and monocytes and is regulated in tumors. It is also known as VEGF co-regulated chemokine 1 (VCC-1) and dendritic cell- and monocyte-attracting chemokine-like protein (DMC). This chemokine is constitutively expressed in the lung. The gene for human CXCL17 is located on chromosome 19.

<span class="mw-page-title-main">Interleukin 8 receptor, beta</span> Mammalian protein found in Homo sapiens

Interleukin 8 receptor, beta is a chemokine receptor. IL8RB is also known as CXCR2, and CXCR2 is now the IUPHAR Committee on Receptor Nomenclature and Drug classification-recommended name.

<span class="mw-page-title-main">Interleukin 8 receptor, alpha</span> Mammalian protein found in Homo sapiens

Interleukin 8 receptor, alpha is a chemokine receptor. This name and the corresponding gene symbol IL8RA have been replaced by the HGNC approved name C-X-C motif chemokine receptor 1 and the approved symbol CXCR1. It has also been designated as CD181. The IUPHAR Committee on Receptor Nomenclature and Drug Classification use the HGNC recommended name, CXCR1.

<span class="mw-page-title-main">C-C chemokine receptor type 6</span> Mammalian protein found in Homo sapiens

Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene. CCR6 has also recently been designated CD196. The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

Ann Richmond is the Ingram Professor of Cancer Research at the Vanderbilt-Ingram Cancer Center and professor of Pharmacology and Dermatology at Vanderbilt University.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000163739 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000058427 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Moser B, Clark-Lewis I, Zwahlen R, Baggiolini M (May 1990). "Neutrophil-activating properties of the melanoma growth-stimulatory activity". The Journal of Experimental Medicine. 171 (5): 1797–1802. doi:10.1084/jem.171.5.1797. PMC   2187876 . PMID   2185333.
  6. ↑ Schumacher C, Clark-Lewis I, Baggiolini M, Moser B (November 1992). "High- and low-affinity binding of GRO alpha and neutrophil-activating peptide 2 to interleukin 8 receptors on human neutrophils". Proceedings of the National Academy of Sciences of the United States of America. 89 (21): 10542–10546. Bibcode:1992PNAS...8910542S. doi: 10.1073/pnas.89.21.10542 . PMC   50375 . PMID   1438244.
  7. ↑ Cochran BH, Reffel AC, Stiles CD (July 1983). "Molecular cloning of gene sequences regulated by platelet-derived growth factor". Cell. 33 (3): 939–947. doi:10.1016/0092-8674(83)90037-5. PMID   6872001. S2CID   38719612.
  8. ↑ Watanabe K, Kinoshita S, Nakagawa H (June 1989). "Purification and characterization of cytokine-induced neutrophil chemoattractant produced by epithelioid cell line of normal rat kidney (NRK-52E cell)". Biochemical and Biophysical Research Communications. 161 (3): 1093–1099. doi:10.1016/0006-291X(89)91355-7. PMID   2662972.
  9. ↑ Haskill S, Peace A, Morris J, Sporn SA, Anisowicz A, Lee SW, et al. (October 1990). "Identification of three related human GRO genes encoding cytokine functions". Proceedings of the National Academy of Sciences of the United States of America. 87 (19): 7732–7736. Bibcode:1990PNAS...87.7732H. doi: 10.1073/pnas.87.19.7732 . PMC   54822 . PMID   2217207.
  10. ↑ Richmond A, Balentien E, Thomas HG, Flaggs G, Barton DE, Spiess J, et al. (July 1988). "Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin". The EMBO Journal. 7 (7): 2025–2033. doi:10.1002/j.1460-2075.1988.tb03042.x. PMC   454478 . PMID   2970963.
  11. 1 2 Tsai HH, Frost E, To V, Robinson S, Ffrench-Constant C, Geertman R, et al. (August 2002). "The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration". Cell. 110 (3): 373–383. doi: 10.1016/S0092-8674(02)00838-3 . PMID   12176324. S2CID   16880392.
  12. ↑ Ravindran A, Sawant KV, Sarmiento J, Navarro J, Rajarathnam K (April 2013). "Chemokine CXCL1 dimer is a potent agonist for the CXCR2 receptor". The Journal of Biological Chemistry. 288 (17): 12244–12252. doi: 10.1074/jbc.m112.443762 . PMC   3636908 . PMID   23479735.
  13. ↑ Iida N, Grotendorst GR (October 1990). "Cloning and sequencing of a new gro transcript from activated human monocytes: expression in leukocytes and wound tissue". Molecular and Cellular Biology. 10 (10): 5596–5599. doi:10.1128/mcb.10.10.5596. PMC   361282 . PMID   2078213.
  14. ↑ Becker S, Quay J, Koren HS, Haskill JS (March 1994). "Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages". The American Journal of Physiology. 266 (3 Pt 1): L278–L286. doi:10.1152/ajplung.1994.266.3.L278. PMID   8166297.
  15. 1 2 Ma K, Yang L, Shen R, Kong B, Chen W, Liang J, et al. (March 2018). "Th17 cells regulate the production of CXCL1 in breast cancer". International Immunopharmacology. 56: 320–329. doi:10.1016/j.intimp.2018.01.026. PMID   29438938. S2CID   3568978.
  16. 1 2 Silva RL, Lopes AH, Guimarães RM, Cunha TM (September 2017). "CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization". Neurobiology of Disease. 105: 109–116. doi:10.1016/j.nbd.2017.06.001. PMID   28587921. S2CID   4916646.
  17. ↑ Devalaraja RM, Nanney LB, Du J, Qian Q, Yu Y, Devalaraja MN, Richmond A (August 2000). "Delayed wound healing in CXCR2 knockout mice". The Journal of Investigative Dermatology. 115 (2): 234–244. doi:10.1046/j.1523-1747.2000.00034.x. PMC   2664868 . PMID   10951241.
  18. ↑ Haghnegahdar H, Du J, Wang D, Strieter RM, Burdick MD, Nanney LB, et al. (January 2000). "The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma". Journal of Leukocyte Biology. 67 (1): 53–62. doi:10.1002/jlb.67.1.53. PMC   2669312 . PMID   10647998.[ permanent dead link ]
  19. ↑ Owen JD, Strieter R, Burdick M, Haghnegahdar H, Nanney L, Shattuck-Brandt R, Richmond A (September 1997). "Enhanced tumor-forming capacity for immortalized melanocytes expressing melanoma growth stimulatory activity/growth-regulated cytokine beta and gamma proteins". International Journal of Cancer. 73 (1): 94–103. doi: 10.1002/(SICI)1097-0215(19970926)73:1<94::AID-IJC15>3.0.CO;2-5 . PMID   9334815.
  20. ↑ Vries MH, Wagenaar A, Verbruggen SE, Molin DG, Dijkgraaf I, Hackeng TH, Post MJ (April 2015). "CXCL1 promotes arteriogenesis through enhanced monocyte recruitment into the peri-collateral space". Angiogenesis. 18 (2): 163–171. doi:10.1007/s10456-014-9454-1. PMID   25490937. S2CID   52835567.
  21. ↑ Chen X, Jin R, Chen R, Huang Z (2018-02-01). "Complementary action of CXCL1 and CXCL8 in pathogenesis of gastric carcinoma". International Journal of Clinical and Experimental Pathology. 11 (2): 1036–1045. PMC   6958037 . PMID   31938199.
  22. ↑ Hsu YL, Chen YJ, Chang WA, Jian SF, Fan HL, Wang JY, Kuo PL (August 2018). "Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1". International Journal of Molecular Sciences. 19 (8): 2427. doi: 10.3390/ijms19082427 . PMC   6121631 . PMID   30115896.
  23. ↑ Spaks A (April 2017). "Role of CXC group chemokines in lung cancer development and progression". Journal of Thoracic Disease. 9 (Suppl 3): S164–S171. doi: 10.21037/jtd.2017.03.61 . PMC   5392545 . PMID   28446981.
  24. ↑ Anisowicz A, Bardwell L, Sager R (October 1987). "Constitutive overexpression of a growth-regulated gene in transformed Chinese hamster and human cells". Proceedings of the National Academy of Sciences of the United States of America. 84 (20): 7188–7192. Bibcode:1987PNAS...84.7188A. doi: 10.1073/pnas.84.20.7188 . PMC   299255 . PMID   2890161.
  25. ↑ Richmond A, Thomas HG (February 1988). "Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution". Journal of Cellular Biochemistry. 36 (2): 185–198. doi:10.1002/jcb.240360209. PMID   3356754. S2CID   10674236.
  26. ↑ Dhawan P, Richmond A (July 2002). "Role of CXCL1 in tumorigenesis of melanoma". Journal of Leukocyte Biology. 72 (1): 9–18. doi:10.1189/jlb.72.1.9. PMC   2668262 . PMID   12101257.
  27. ↑ Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS (January 2009). "Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1". The American Journal of Pathology. 174 (1): 164–176. doi:10.2353/ajpath.2009.080350. PMC   2631329 . PMID   19095949.
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