Note | CXCL4L1 precursor: 104 amino acids (aa), 11553 Da; CXCL4L1 mature: 70 aa, 7805.8 Da. |
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Description | CXCL4L1 is a member of the CXC chemokine family of chemoattractant cytokines. CXCL4L1 is a non-ELR CXC chemokine, meaning that it lacks the sequence glutamic acid-leucine-arginine just in front of the two NH2-terminally located conserved cysteine residues. |
Expression | Blood platelets release both CXCL4 and CXCL4L1 after activation. The exact location of CXCL4L1 inside the platelet is not yet determined, whereas platelet CXCL4 is stored in the alpha-granules. In other cell types as well, CXCL4 is stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 is continuously synthesized and secreted through a constitutive pathway (Lasagni et al., 2007). For instance, human aortic smooth muscle cells and human coronary smooth muscle cells constitutively release CXCL4L1. Specific cancer cell lines have also been shown to produce CXCL4L1. Secretion of CXCL4L1 in tumoral tissue was evidenced in vitro on stimulated osteosarcoma cells through the use of ELISA and further corroborated by immunohistochemical staining of different human sarcoma tissue sections (osteosarcoma, leiomyosarcoma and liposarcoma) (Vandercappellen et al., 2007). Furthermore, CXCL4L1 was strongly detected in colorectal adenocarcinoma biopsy specimens (Verbeke et al., 2010). |
Localisation | Secreted. |
Function | CXCL4L1 has been described to be a strong inhibitor of angiogenesis. Together with its potential to chemoattract T cells, natural killer cells and immature dendritic cells, the vascular effects contribute to the antitumoral action of CXCL4L1 (Struyf et al., 2011). Struyf et al. (Struyf et al., 2007) indeed indicated the angiostatic platelet factor to exert an antitumoral effect by inhibiting branching of the vascular network and metastasis. Considering neutrophils and monocytes, CXCL4L1 as opposed to CXCL4 would not attract these pro-tumoral phagocytes (Vandercappellen et al., 2007). Lasagni et al. identified a splice variant of CXCR3, which was named CXCR3B, as a functional GPCR for CXCL4 (Lasagni et al., 2003). Currently, both CXCL4 and CXCL4L1 are known to activate CXCR3A, as well as CXCR3B (Mueller et al., 2008; Struyf et al., 2011; Van Raemdonck et al., 2014). In general, proliferative and positive migratory effects are supposed to be mediated by CXCR3A, whereas inhibition of chemotaxis, anti-proliferative and apoptotic effects are postulated to be provoked via CXCR3B (Lasagni et al., 2003). Besides endothelial cells and T cells, CXCR3 expressing cell types can be extended to fibroblasts, mesangial cells, airway epithelial and smooth muscle cells, pneumocytes and several sarcoma, carcinoma and myeloma cell types (Billottet et al., 2013). CXCL4 exerts its action through many different mechanisms, including binding to GAG and heteromultimerisation with other chemokines and growth factors, whereas in the case of CXCL4L1 its distorted structure and unique protruding C-terminal helix are assumed to conflict with this mode of action. The open formation characteristic of CXCL4L1 decreases GAG-binding, however simultaneously enhancing anti-angiogenic and anti-tumoral effects (Dubrac et al., 2010; Kuo et al., 2013). Additionally, CXCL4L1 forms more stable homodimers due to a loss in positive charge. This gained stability is likely to interfere with the ability to form heteromers which requires initial dissociation of the homomultimers (Kuo et al., 2013). |
Homology | CXCL4L1 is a non-allelic variant of CXCL4. Unlike CXCL4, its variant appears only in primates. In men, mature proteins only differ in 3 amino acids. On the other hand, the signal peptide of human CXCL4L1 displays 38% amino acid divergence compared to human CXCL4, affecting its subcellular localization and regulated secretion mechanism, as was described by Lasagni et al. (Lasagni et al., 2007). |
CXCR3, a double-edged sword in tumor progression and angiogenesis. |
Billottet C, Quemener C, Bikfalvi A. |
Biochim Biophys Acta. 2013 Dec;1836(2):287-95. doi: 10.1016/j.bbcan.2013.08.002. Epub 2013 Aug 27. (REVIEW) |
PMID 23994549 |
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PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function. |
De Sutter J, Van de Veire NR, Struyf S, Philippe J, De Buyzere M, Van Damme J. |
PLoS One. 2012;7(2):e31343. doi: 10.1371/journal.pone.0031343. Epub 2012 Feb 23. |
PMID 22384011 |
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Functional divergence between 2 chemokines is conferred by single amino acid change. |
Dubrac A, Quemener C, Lacazette E, Lopez F, Zanibellato C, Wu WG, Bikfalvi A, Prats H. |
Blood. 2010 Nov 25;116(22):4703-11. doi: 10.1182/blood-2010-03-274852. Epub 2010 Aug 5. |
PMID 20688960 |
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Structural and functional comparison of the genes for human platelet factor 4 and PF4alt. |
Eisman R, Surrey S, Ramachandran B, Schwartz E, Poncz M. |
Blood. 1990 Jul 15;76(2):336-44. |
PMID 1695112 |
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Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis. |
Furuya M, Tanaka R, Miyagi E, Kami D, Nagahama K, Miyagi Y, Nagashima Y, Hirahara F, Inayama Y, Aoki I. |
Cancer Biol Ther. 2012 Jun;13(8):671-80. doi: 10.4161/cbt.20084. Epub 2012 Jun 1. |
PMID 22555803 |
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Identification and characterization of PF4varl, a human gene variant of platelet factor 4. |
Green CJ, Charles RS, Edwards BF, Johnson PH. |
Mol Cell Biol. 1989 Apr;9(4):1445-51. |
PMID 2725510 |
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Alternative C-terminal helix orientation alters chemokine function: structure of the anti-angiogenic chemokine, CXCL4L1. |
Kuo JH, Chen YP, Liu JS, Dubrac A, Quemener C, Prats H, Bikfalvi A, Wu WG, Sue SC. |
J Biol Chem. 2013 May 10;288(19):13522-33. doi: 10.1074/jbc.M113.455329. Epub 2013 Mar 27. |
PMID 23536183 |
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An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. |
Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P. |
J Exp Med. 2003 Jun 2;197(11):1537-49. |
PMID 12782716 |
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PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion. |
Lasagni L, Grepin R, Mazzinghi B, Lazzeri E, Meini C, Sagrinati C, Liotta F, Frosali F, Ronconi E, Alain-Courtois N, Ballerini L, Netti GS, Maggi E, Annunziato F, Serio M, Romagnani S, Bikfalvi A, Romagnani P. |
Blood. 2007 May 15;109(10):4127-34. Epub 2007 Jan 11. |
PMID 17218382 |
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CXCL4-induced migration of activated T lymphocytes is mediated by the chemokine receptor CXCR3. |
Mueller A, Meiser A, McDonagh EM, Fox JM, Petit SJ, Xanthou G, Williams TJ, Pease JE. |
J Leukoc Biol. 2008 Apr;83(4):875-82. doi: 10.1189/jlb.1006645. Epub 2008 Jan 3. |
PMID 18174362 |
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Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. |
Pradelli E, Karimdjee-Soilihi B, Michiels JF, Ricci JE, Millet MA, Vandenbos F, Sullivan TJ, Collins TL, Johnson MG, Medina JC, Kleinerman ES, Schmid-Alliana A, Schmid-Antomarchi H. |
Int J Cancer. 2009 Dec 1;125(11):2586-94. doi: 10.1002/ijc.24665. |
PMID 19544560 |
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CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis. |
Prats AC, Van den Berghe L, Rayssac A, Ainaoui N, Morfoisse F, Pujol F, Legonidec S, Bikfalvi A, Prats H, Pyronnet S, Garmy-Susini B. |
Microvasc Res. 2013 Sep;89:25-33. doi: 10.1016/j.mvr.2013.05.005. Epub 2013 Jun 4. |
PMID 23747987 |
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Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis. |
Struyf S, Burdick MD, Peeters E, Van den Broeck K, Dillen C, Proost P, Van Damme J, Strieter RM. |
Cancer Res. 2007 Jun 15;67(12):5940-8. |
PMID 17575164 |
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Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. |
Struyf S, Salogni L, Burdick MD, Vandercappellen J, Gouwy M, Noppen S, Proost P, Opdenakker G, Parmentier M, Gerard C, Sozzani S, Strieter RM, Van Damme J. |
Blood. 2011 Jan 13;117(2):480-8. doi: 10.1182/blood-2009-11-253591. Epub 2010 Oct 27. |
PMID 20980681 |
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CXCL4L1 and CXCL4 signaling in human lymphatic and microvascular endothelial cells and activated lymphocytes: involvement of mitogen-activated protein (MAP) kinases, Src and p70S6 kinase. |
Van Raemdonck K, Gouwy M, Lepers SA, Van Damme J, Struyf S. |
Angiogenesis. 2014 Jul;17(3):631-40. doi: 10.1007/s10456-014-9417-6. Epub 2014 Jan 28. |
PMID 24469069 |
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The COOH-terminal peptide of platelet factor-4 variant (CXCL4L1/PF-4var47-70) strongly inhibits angiogenesis and suppresses B16 melanoma growth in vivo. |
Vandercappellen J, Liekens S, Bronckaers A, Noppen S, Ronsse I, Dillen C, Belleri M, Mitola S, Proost P, Presta M, Struyf S, Van Damme J. |
Mol Cancer Res. 2010 Mar;8(3):322-34. doi: 10.1158/1541-7786.MCR-09-0176. Epub 2010 Mar 9. |
PMID 20215425 |
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Expression of angiostatic platelet factor-4var/CXCL4L1 counterbalances angiogenic impulses of vascular endothelial growth factor, interleukin-8/CXCL8, and stromal cell-derived factor 1/CXCL12 in esophageal and colorectal cancer. |
Verbeke H, De Hertogh G, Li S, Vandercappellen J, Noppen S, Schutyser E, El-Asrar AA, Opdenakker G, Van Damme J, Geboes K, Struyf S. |
Hum Pathol. 2010 Jul;41(7):990-1001. doi: 10.1016/j.humpath.2009.09.021. Epub 2010 Mar 23. |
PMID 20334899 |
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