CXCL12 (chemokine (C-X-C motif) ligand 12)

2015-08-01   Giulia Gentile , Maria Guarnaccia , Sebastiano Cavallaro 

Functional Genomics Unit, Institute of Neurogical Sciences, National Research Council, Catania, Italy

Identity

HGNC
LOCATION
10q11.21
LOCUSID
ALIAS
IRH,PBSF,SCYB12,SDF1,TLSF,TPAR1
FUSION GENES

Abstract

Review on CXCL12, with data on DNA, on the protein encoded, and where the gene is implicated.

DNA/RNA

Atlas Image
Figure 1 Schematic structure of the four exons of human CXCL12 (exon1: 153bp; exon2: 118bp; exon3: 87bp; exon4: 3191bp). Two of them are made up not only of coding regions (in green color) but also of non-coding ones (in red color).

Description

The CXCL12 gene consists of 4 exons spanning 14.94 kb on the chromosome 10 at band q11.21 (reverse strand) (Figure 1).

Transcription

Alternative splicing results in eight transcript variants (Table 1), as shown in Ensembl database. Among them, six correspond to as many protein isoforms (Yu et al., 2006).

Pseudogene

No known pseudogenes.

Proteins

Atlas Image

Description

CXCL12 gene encodes a stromal cell-derived alpha chemokine, also known as SDF1, a member of the intercrine family. This family is defined by the location of the first two cysteine residues in the sequence, which are separated by one amino acid (C-X-C chemokine)(Hromas, 1997). Six protein isoforms have been identified in human: Alpha, Beta, Gamma, Delta, Epsilon and Theta (Table 2; Figure 2), produced by alternative splicing events (Yu et al., 2006). In particular Alpha and Beta isoforms, secreted as full-length molecules, undergo to post-translational modifications by a proteolytic cleavage, becoming respectively processed forms SDF-1-alpha(3-67) and SDF-1-beta(3-72)(De la Luz Sierra et al., 2004). The Beta isoform has been chosen as the canonical sequence and, together with Alpha isoform, is ubiquitously expressed in liver, pancreas and spleen. The Gamma Isoform is mainly expressed in heart, while the isoforms Delta, Epsilon and Theta are mainly expressed in pancreas. In the developmental stage, the isoform Alpha is ubiquitously expressed in fetal tissues, Beta and Delta isoforms in fetal spleen and liver, while Gamma and Theta isoforms are weakly detected in fetal kidney (Yu et al., 2006).
Atlas Image
Figure 2 The figure shows (A)the molecule processing of CXCL12 beta isoform sequence, in which the potential signal peptide is marked in red color while the polypeptide chain in blue color (data obtained from UniProtKB database);(B) the multiple sequence alignment of the six CXCL12 isoforms. For each isoform, after the 88 identical positions there are a certain number of different residues, highlighted in light blue color. (Alignment produced by CLC Sequence Viewer 7.0 from CLCbio - QIAGEN Company, using Clustal Omega multiple alignment program). SDF-1-alpha(3-67) and SDF-1-beta(3-72), processed by post-translational proteolytic cleavage, are marked by yellow and orange boxes respectively (data on both sequences belong to UniProtKB database).

Expression

CXCL12 is widely expressed in a variety of tissue types, such as heart, liver, spleen, kidney, brain, skeletal muscle, endothelium, epithelium, lymphoid organs, stem cells as well as overexpressed in cancer cells (Kryczek et al., 2007; Teicher and Fricker, 2010).

Localisation

Extracellular region.

Function

The CXCL12 protein functions as a ligand for two seven-transmembrane receptors (7-TMRs). The first one is the chemokine (C-X-C motif) receptor 4 (CXCR4), a monogamous receptor that signals through heterotrimeric G proteins and beta-arrestin; the second one is the chemokine (C-X-C motif) receptor 7 (CXCR7), a non-monogamous receptor that does not activate G-protein-mediated signal transduction but signals only through beta-arrestin (Oberlin et al., 1996; Rajagopal et al., 2010; Sun et al., 2010; Zhu et al., 2012; Sanchez-Martin et al., 2013). In particular, CXCL12 has a higher affinity of binding to CXCR7 than to CXCR4 (Zhu et al., 2012), even if its affinity to CXCR7 seems to be reduced by the expression of CXCR4 at the membrane (Sanchez-Martin et al., 2013). CXCL12 is secreted in the extracellular space as monomeric and dimeric forms, which can trigger different effects on cell signaling (Ray et al., 2012). In fact, whereas CXCR4 binds both monomeric and dimeric forms, CXCR7 binds preferentially the dimeric one (Sanchez-Martin et al., 2013). For example, dimeric CXCL12 form induces calcium mobilization but fails to promote chemotaxis, which is induced by the monomer-based interactions (Ray et al., 2012; Sanchez-Martin et al., 2013). Many others cellular functions depend on CXCL12 activity, including embryogenesis, apoptosis and survival, immune response, tissue homeostasis, angiogenesis, calcium ion homeostasis, clathrin-mediated endocytosis, cytoskeletal rearrangement, cell proliferation and migration, tumor growth and metastasis (Vlahakis et al., 2002; Goda et al., 2006; Petit et al., 2007; Khan et al., 2008; Agle et al., 2010; Drury et al.,2010; Karin, 2010; Kremer, 2010; Sun et al., 2010; Zhu et al., 2012).

Homology

The CXCL12 Gene Tree shows a great evolutionary conservation across species (Figure 3). The internal nodes of the phylogenetic tree are annotated for duplication (red boxes) and speciation (blue boxes) events, which correspond to paralogs and orthologs homologous genes respectively.
Atlas Image
Figure 3 The CXCL12 Gene Tree shows the maximum likelihood phylogenetic tree representing the evolutionary history of the CXCL12 gene, constructed using the alignment of a CXCL12 representative protein for each species (green bars). The Gene tree has been generated by Ensembl (GeneTree ENSGT00390000014056 - August 2015) using the Gene Orthology/Paralogy prediction method pipeline (Vilella et al., 2009).

Mutations

Note

NOTE It has been suggested that a single nucleotide polymorphism (SNP)in the 3 untranslated region of SDF-1-beta transcript is associated not only with a delayed onset (Winkler et al., 1998) and a modest protective effect against infection and progression of AIDS (Modi et al., 2005), but also with the early onset of type 1 diabetes (Dubois-Laforgue et al., 2001) and with an increased likelihood of developing several cancers (as lung, breast, colorectal and prostate)(Ma et al., 2012; Shi et al., 2013). This could be explained by an increased level and stability of SDF-1-beta transcript as effect of this mutation (Garcia-Moruja et al., 2009).

Somatic

A SNP consisting of a G-to-A transition at position 801, counting from the ATG start codon in the 3 UTR of the Genbank reference sequence L36033, was represented in the SDF-1-beta transcript but not in the SDF-1-alpha transcript (Winkler et al., 1998). The mutation CXCL12-G801A-3 Prime UTR, also known as SDF1-3-prime-A, located at chromosome 10 position 44873550 on Assembly GRCh37, has been classified as pathogenic variant (dbSNP: rs387906400)related to the phenotype Human immunodeficiency virus type 1, resistance to (OMIM: 600835.0001).

Implicated in

Entity name
Lung cancer
Note
The CXCL12 expression showed an increase in lung cancer cell lines (small cell lung cancers and non-small cell lung cancers) compared to non-malignant human bronchial epithelial cell ones. This overexpression was positively but weakly correlated with those of CXCR4 or CXCR7, suggesting that CXCL12 may differentially interact with its receptors depending on the cellular context (Imai et al., 2010). Furthermore, different evidences support the involvement of the CXCL12/CXCR4 axis, but not CXCL12/CXCR7, in the metastatic behavior of non-small cell lung cancer, suggesting their potential use as prognostic markers and drug targets (Paratore et al., 2011; Cavallaro, 2013; Choi et al., 2014).
Entity name
Breast cancer
Note
The CXCL12 expression has been shown to stimulate breast cancer cells proliferation and promote tumor growth (Allinen et al., 2004; Duda et al., 2011). Moreover, a CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3 untranslated region) was associated with an increased susceptibility to breast cancer (Dimberg et al., 2007). The interactions of CXCL12/CXCR4 seems to have a critical role in determining the metastatic destination of breast cancer metastasis (Muller et al., 2001; Hinton et al., 2011), while the CXCR7 expression has been linked to the ability of tumor cells to produce lung and brain metastasis (Sun et al., 2010). In a recent study, the expression profiles of the six CXCL12 isoforms and both receptors have been investigated in a large clinical cohort and common breast cancer cell lines. As result, isoform-specific differences in expression and breast cancer outcomes have been established, while CXCR4 and CXCR7 showed an opposite pattern in cancer as compared with normal and further differences between hormone receptor status and molecular subtypes (Zhao et al., 2014).
Entity name
Other malignancies
Note
The importance of CXCL12 pathways in the proliferation, growth and metastasis processes has been assessed for many other types of tumors, among which prostate cancer (Vaday et. al., 2004; Zhang et al., 2008; Sun et al., 2010; Duda et al., 2011), pancreatic adenocarcinoma (Shen et al., 2013; Wu et al., 2013), neuroblastoma (Zagozdzon et al.,2008; Liberman et al., 2012), glioblastoma (Gatti et al., 2013; Wurth et al., 2014; Yao et al., 2015), colorectal cancer (Brand et al., 2005; Akishima-Fukasawa et al., 2009; Drury et al., 2010), melanoma (Scala et al., 2005; Toyozawa et al.,2012; Mitchell et al., 2014), bladder cancer (Retz et al., 2005; Shen et al., 2013), esophageal cancer (Sasaki et al., 2008; Wang et al., 2009; Tachezy et al., 2013), renal cancer (Pan et al., 2006; Ieran et al., 2014) and ovarian cancer (Popple et al., 2012).
Entity name
Human Immunodeficiency Virus-type 1 (HIV-1) infection
Note
Since the discovery of the leukocyte-derived seven-transmembrane domain receptor (LESTR) twenty years ago (Loetscher et al., 1994) and of its function of co-receptor (termed fusin) for lymphocyte-tropic HIV-1 strains, the role of this chemokine receptor in modulating cell permissiveness to the infection was delineated in few years(Feng et al., 1996). At the same time, was reported the identification of the SDF-1 human chemokine as the natural ligand for LESTR/fusin protein, so named CXCR4, and its function of infection inhibitor by lymphocyte-tropic HIV-1 strains (Bleul et al., 1996 ; Oberlin et al., 1996). It was clarified that the HIV-1 infection requires expression of CD4, as primary receptor, and the CXCR4 as entry co-factor at the target cell surface; the engagement of these receptors by the HIV-1 envelope glycoprotein is essential for membrane fusion and, HIV infection can be prevented by HIV co-receptor antagonists (Davis et al., 1997). The HIV suppressive activity of SDF-1, by inhibition of HIV replication, was explained by a SDF-1 alpha-dependent internalization of the CXCR4 (Amara et al., 1997). Furthermore, as previously described in the mutations section, the SDF-1-beta chemokine gene variant in the homozygous state (SDF1-3A/3A), has been correlate to a delay of the AIDS onset (Winkler et al., 1998). During these years, different CXCR4 antagonists have reached later stage clinical trials but no one is currently underway (Henrich and Kuritzkes, 2013).
Entity name
WHIM Syndrome
Note
WHIM is an acronym for an immunodeficiency disorder characterized by (w)arts, (h)ypogammaglobulinemia, (i)nfections and (m)yelokathexis symptoms. In most cases, it is caused by an inherited mutation affecting the CXCR4 gene (Hernandez et al., 2003; Liu et al., 2012).
Entity name
Autoimmune Diseases
Note
CXCL12 functions as an anti-inflammatory chemokine during autoimmune inflammatory responses suggesting the use of CXCL12-based therapies for autoimmune inflammatory diseases (Karin, 2010; Villalvilla et al., 2014).

Bibliography

Pubmed IDLast YearTitleAuthors
203480952010Calcium mobilization triggered by the chemokine CXCL12 regulates migration in wounded intestinal epithelial monolayers.Agle KA et al
196058142009Prognostic significance of CXCL12 expression in patients with colorectal carcinoma.Akishima-Fukasawa Y et al
152611392004Molecular characterization of the tumor microenvironment in breast cancer.Allinen M et al
92070081997HIV coreceptor downregulation as antiviral principle: SDF-1alpha-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication.Amara A et al
87522801996The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry.Bleul CC et al
161251702005CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation.Brand S et al
233220212013CXCR4/CXCL12 in non-small-cell lung cancer metastasis to the brain.Cavallaro S et al
240259712014CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells.Choi YH et al
93625411997Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5.Davis CB et al
145257752004Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity.De La Luz Sierra M et al
171435422007Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients.Dimberg J et al
208775732010CXCL12 chemokine expression and secretion regulates colorectal carcinoma cell anoikis through Bim-mediated intrinsic apoptosis.Drury LJ et al
113344292001A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes.Dubois-Laforgue D et al
213499982011CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies?Duda DG et al
86290221996HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.Feng Y et al
196017732009Molecular phenotype of CXCL12beta 3'UTR G801A polymorphism (rs1801157) associated to HIV-1 disease progression.Garcia-Moruja C et al
241575752013Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity.Gatti M et al
168773472006Matrix metalloproteinase-1 produced by human CXCL12-stimulated natural killer cells.Goda S et al
232906282013HIV-1 entry inhibitors: recent development and clinical use.Henrich TJ et al
126925542003Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.Hernandez PA et al
188140422010Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain.Hinton CV et al
249917622014CXCR4 and CXCR7 transduce through mTOR in human renal cancer cells.Ieranò C et al
203780032010Clinicopathological and therapeutic significance of CXCL12 expression in lung cancer.Imai H et al
205017492010The multiple faces of CXCL12 (SDF-1alpha) in the regulation of immunity during health and disease.Karin N et al
185839902008The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein.Khan MZ et al
237986752013CXCR4 chemokine receptor signaling induces apoptosis in acute myeloid leukemia cells via regulation of the Bcl-2 family members Bcl-XL, Noxa, and Bak.Kremer KN et al
169432402007Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis.Kryczek I et al
229162932012Involvement of the CXCR7/CXCR4/CXCL12 axis in the malignant progression of human neuroblastoma.Liberman J et al
225962582012WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.Liu Q et al
82767991994Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes.Loetscher M et al
112420362001Involvement of chemokine receptors in breast cancer metastasis.Müller A et al
227625252012CXCL12 G801A polymorphism contributes to cancer susceptibility: a meta-analysis.Ma XY et al
251303952014Protein expression of the chemokine receptor CXCR4 and its ligand CXCL12 in primary cutaneous melanoma--biomarkers of potential utility?Mitchell B et al
161778292005Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study.Modi WS et al
87522811996The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1.Oberlin E et al
170837232006Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis.Pan J et al
224301352011CXCR4 and CXCL12 immunoreactivities differentiate primary non-small-cell lung cancer with or without brain metastases.Paratore S et al
175601692007The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis.Petit I et al
224152332012The chemokine, CXCL12, is an independent predictor of poor survival in ovarian cancer.Popple A et al
200186512010Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7.Rajagopal S et al
221421942012Secreted CXCL12 (SDF-1) forms dimers under physiological conditions.Ray P et al
155402052005CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells.Retz MM et al
231535752013CXCR7 impact on CXCL12 biology and disease.Sánchez-Martín L et al
181769152008Expression of CXCL12 and its receptor CXCR4 correlates with lymph node metastasis in submucosal esophageal cancer.Sasaki K et al
157560072005Expression of CXCR4 predicts poor prognosis in patients with malignant melanoma.Scala S et al
241758342013CXCL12-CXCR4 promotes proliferation and invasion of pancreatic cancer cells.Shen B et al
235260792013CXCR4-mediated Stat3 activation is essential for CXCL12-induced cell invasion in bladder cancer.Shen HB et al
244826422013CXCL12-G801A polymorphism modulates risk of colorectal cancer in Taiwan.Shi MD et al
208390322010CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression.Sun X et al
240742512013CXCR7 expression in esophageal cancer.Tachezy M et al
204840212010CXCL12 (SDF-1)/CXCR4 pathway in cancer.Teicher BA et al
232093382012Chemokine receptor CXCR4 is a novel marker for the progression of cutaneous malignant melanomas.Toyozawa S et al
153282062004CXCR4 and CXCL12 (SDF-1) in prostate cancer: inhibitory effects of human single chain Fv antibodies.Vaday GG et al
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249500162014SDF-1 signaling: a promising target in rheumatic diseases.Villalvilla A et al
124219312002G protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways.Vlahakis SR et al
249042892014CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment.Würth R et al
195501282009Expression of CXCL12/CXCR4 and its correlation to prognosis in esophageal squamous cell carcinoma.Wang DF et al
94305901998Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. ALIVE Study, Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC)Winkler C et al
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261796132016CXCL12/CXCR4 Axis Upregulates Twist to Induce EMT in Human Glioblastoma.Yao C et al
166268952006Identification and expression of novel isoforms of human stromal cell-derived factor 1.Yu L et al
182929392008Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma.Zagozdzon R et al
189836832008Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancer.Zhang S et al
248366492014A Comprehensive Analysis of CXCL12 Isoforms in Breast Cancer1,2.Zhao S et al
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Other Information

Locus ID:

NCBI: 6387
MIM: 600835
HGNC: 10672
Ensembl: ENSG00000107562

Variants:

dbSNP: 6387
ClinVar: 6387
TCGA: ENSG00000107562
COSMIC: CXCL12

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000107562ENST00000343575P48061
ENSG00000107562ENST00000374426P48061
ENSG00000107562ENST00000374429P48061
ENSG00000107562ENST00000395793P48061
ENSG00000107562ENST00000395794P48061
ENSG00000107562ENST00000395795P48061

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Axon guidanceKEGGko04360
Leukocyte transendothelial migrationKEGGko04670
Cytokine-cytokine receptor interactionKEGGhsa04060
Axon guidanceKEGGhsa04360
Leukocyte transendothelial migrationKEGGhsa04670
Pathways in cancerKEGGhsa05200
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Intestinal immune network for IgA productionKEGGko04672
Intestinal immune network for IgA productionKEGGhsa04672
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Signal TransductionREACTOMER-HSA-162582
Signaling by ERBB4REACTOMER-HSA-1236394
Nuclear signaling by ERBB4REACTOMER-HSA-1251985
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
Chemokine receptors bind chemokinesREACTOMER-HSA-380108
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (i) signalling eventsREACTOMER-HSA-418594

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164783958alemtuzumabChemicalClinicalAnnotationassociatedPD27173875
PA446169Leukemia, Lymphocytic, Chronic, B-CellDiseaseClinicalAnnotationassociatedPD27173875
PA448926chlorambucilChemicalClinicalAnnotationassociatedPD27173875
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD27173875
PA449655fludarabineChemicalClinicalAnnotationassociatedPD27173875
PA451100prednisoneChemicalClinicalAnnotationassociatedPD27173875
PA451261rituximabChemicalClinicalAnnotationassociatedPD27173875
PA451879vincristineChemicalClinicalAnnotationassociatedPD27173875

References

Pubmed IDYearTitleCitations
158826172005Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.1211
191986092009Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.460
152868102004Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.398
161073332005The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes.334
156080622004Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway.323
119121622002Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone.303
210416592010Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts.244
158886872005Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis.241
223707172012HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4.204
226833072013A review on CXCR4/CXCL12 axis in oncology: no place to hide.190

Citation

Giulia Gentile ; Maria Guarnaccia ; Sebastiano Cavallaro

CXCL12 (chemokine (C-X-C motif) ligand 12)

Atlas Genet Cytogenet Oncol Haematol. 2015-08-01

Online version: http://atlasgeneticsoncology.org/gene/40219/cxcl12-(chemokine-(c-x-c-motif)-ligand-12)