ITGA9 (integrin, alpha 9)

2013-10-01   Carla Molist , Ana Almazán-Moga , Isaac Vidal , Aroa Soriano , Luz Jubierre , Miguel F Segura , Josep Sánchez de Toledo , Soledad Gallego , Josep Roma 

Laboratory of Translational Research in Paediatric Cancer, Vall dHebron Research Institute, Barcelona, Spain (CM, AAM, IV, AS, LJ, MFS, JSdT, SG, JR); Paediatric Oncology, Haematology, Vall dHebron Hospital, Barcelona, Spain (JSdT, SG)

Identity

HGNC
LOCATION
3p22.2
LOCUSID
ALIAS
ALPHA-RLC,ITGA4L,RLC
FUSION GENES

DNA/RNA

Atlas Image

Description

Chromosome 3: 37493606-37865005; forward strand. Segons omim: 3:37493812 - 37861280.

Transcription

Exons: 28; Coding exons: 28; Transcript length: 7889 bps; Translation length: 1035 residues.
4 splice variants described (7889, 2282, 609 and 428bp), three of which with protein translation (1035, 632 and 609 aa).

Proteins

Note

Alpha9-Integrin.
Atlas Image

Description

Alpha-integrins, such as Alpha9-Integrin, are cell surface glycoproteins that contain a large N-terminal extracellular domain with 7 conserved repeats of putative metal-binding domains, a transmembrane segment, and a short C-terminal cytoplasmic tail. ITGA9, like ITGA4, lacks the domain I and the post-translational cleavage that usually occurs in the rest of alpha-integrins. Alpha9-Integrin forms a functional heterodimer with beta1-integrin.

Expression

ITGA9 expression is widely distributed in normal human epithelia and muscle. For instance, it has been found in airway epithelium, basal layer of squamous epithelium, smooth muscle and skeletal muscle. Furthermore, its expression has been found in hepatocytes, breast tissue, neutrophils and polymorphonuclear leukocytes.

Localisation

Cell membrane.

Function

Adhesion with extracellular-matrix proteins, cell-cell interactions and signal transduction. ITGA9 has been shown to bind a plethora of ligands: tenascin, VCAM-1, osteopontin, uPAR, plasmin, angiostatin, several ADAMs (ADAM1, ADAM2, ADAM3, ADAM7, ADAM8, ADAM9, ADAM12, ADAM15, ADAM28 and ADAM33), EMILIN1, fibronectin, VEGF-A, VEGF-C and VEGF-D.
Alpha9 knockout mice died from respiratory failure before day 12 after birth and showed chylothorax, defective lymphatic and venous valve morphogenesis, impaired development of neutrophils, improper re-epithelialisation during cutaneous wound-healing, impaired bone resorption and abnormal osteoclasts.
In cancer, the heterodimer alpha9-beta1 has recently been shown to have an oncogenic role by inducing epithelial-mesenchymal transition and cell migration and metastatic ability in several cancers such as glioma, breast, colon and rhabdomyosarcoma. However, other authors have reported a tumour suppressor function for ITGA9 in a wide variety of tumours based on deletion or methylation states in varying percentages of patients. Furthermore, a very small percentage of patients (1%) with point mutations has also been reported.

Homology

Alpha- and beta-integrins are completely distinct, with no detectable homology between them. Sequence identity among alpha-integrins is around 45%. All alpha-integrins are thought to have evolved from a common ancestor. Among all alpha-subunits, alpha-9 shows the greatest homology with alpha-4.

Mutations

Atlas Image

Implicated in

Entity name
Small cell lung cancer (SCLC)
Note
Yamakawa et al. (1993) identified a region of homozygous deletions in chromosome 3p21.3 in lung cancer cell lines, where the ITGA9 gene is located. Furthermore, Hibi et al. (1994) reported an upregulation of the ITGA9 gene in SCLC cell lines and primary tumours, suggesting that an altered expression of the ITGA9 may contribute to the phenotype of this cancer.
An activation of ITGA9 expression has been shown in different human tumours and cancer cells, for example small cell lung cancer, medulloblastoma, astrocytoma and glioblastoma.
On the other hand, several genetic and epigenetic aberrations (deletions and methylations) of ITGA9 have been described in several types of cancer such as kidney, lung, breast, ovarian, cervical, prostate and colorectal.

Bibliography

Pubmed IDLast YearTitleAuthors
118826572002Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions.Eto K et al
223706352013Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition.Gupta SK et al
82902721994Aberrant upregulation of a novel integrin alpha subunit gene at 3p21.3 in small cell lung cancer.Hibi K et al
227817462012The newcomer in the integrin family: integrin α9 in biology and cancer.Høye AM et al
118397642002The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing.Liao YF et al
225450972012Co-expression of α9β1 integrin and VEGF-D confers lymphatic metastatic ability to a human breast cancer cell line MDA-MB-468LN.Majumder M et al
204357422010Human neutrophil integrin alpha9beta1: up-regulation by cell activation and synergy with beta2 integrins during adhesion to endothelium under flow.Mambole A et al
229767972012Notch-mediated induction of N-cadherin and α9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells.Masià A et al
219755482011Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors.Mostovich LA et al
82451321993Sequence and tissue distribution of the integrin alpha 9 subunit, a novel partner of beta 1 that is widely distributed in epithelia and muscle.Palmer EL et al
105775131999alpha9beta1 integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers.Shang T et al
175431362007The integrins.Takada Y et al
102090341999The integrin alpha9beta1 mediates adhesion to activated endothelial cells and transendothelial neutrophil migration through interaction with vascular cell adhesion molecule-1.Taooka Y et al
219464322012Integrin α9β1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway.Veeravalli KK et al
83812201993Frequent homozygous deletions in lung cancer cell lines detected by a DNA marker located at 3p21.3-p22.Yamakawa K et al

Other Information

Locus ID:

NCBI: 3680
MIM: 603963
HGNC: 6145
Ensembl: ENSG00000144668

Variants:

dbSNP: 3680
ClinVar: 3680
TCGA: ENSG00000144668
COSMIC: ITGA9

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000144668ENST00000264741Q13797
ENSG00000144668ENST00000411817H7C2L1
ENSG00000144668ENST00000422441E9PDS3

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Focal adhesionKEGGko04510
ECM-receptor interactionKEGGko04512
Cell adhesion molecules (CAMs)KEGGko04514
Regulation of actin cytoskeletonKEGGko04810
Focal adhesionKEGGhsa04510
ECM-receptor interactionKEGGhsa04512
Cell adhesion molecules (CAMs)KEGGhsa04514
Regulation of actin cytoskeletonKEGGhsa04810
Hypertrophic cardiomyopathy (HCM)KEGGko05410
Hypertrophic cardiomyopathy (HCM)KEGGhsa05410
Arrhythmogenic right ventricular cardiomyopathy (ARVC)KEGGko05412
Arrhythmogenic right ventricular cardiomyopathy (ARVC)KEGGhsa05412
Dilated cardiomyopathyKEGGko05414
Dilated cardiomyopathyKEGGhsa05414
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Extracellular matrix organizationREACTOMER-HSA-1474244
ECM proteoglycansREACTOMER-HSA-3000178
Integrin cell surface interactionsREACTOMER-HSA-216083
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
L1CAM interactionsREACTOMER-HSA-373760
Signal transduction by L1REACTOMER-HSA-445144

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443635Cardiovascular DiseasesDiseaseVariantAnnotationnot associatedPD24816038
PA446021Vascular DiseasesDiseaseVariantAnnotationnot associatedPD24816038
PA451089pravastatinChemicalVariantAnnotationnot associatedPD24816038

References

Pubmed IDYearTitleCitations
196866792009Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.122
155906422005The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1.63
204791552010Blood pressure and hypertension are associated with 7 loci in the Japanese population.63
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
194038222009Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration.52
160052002005Distinct structural requirements for binding of the integrins alphavbeta6, alphavbeta3, alphavbeta5, alpha5beta1 and alpha9beta1 to osteopontin.37
210714502011Vascular endothelial growth factor A (VEGF-A) induces endothelial and cancer cell migration through direct binding to integrin {alpha}9{beta}1: identification of a specific {alpha}9{beta}1 binding site.33
194943272009Alpha9 integrin and its ligands constitute critical joint microenvironments for development of autoimmune arthritis.31
204142542010Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population.29
194788192009A genome-wide association study identifies ITGA9 conferring risk of nasopharyngeal carcinoma.27

Citation

Carla Molist ; Ana Almazán-Moga ; Isaac Vidal ; Aroa Soriano ; Luz Jubierre ; Miguel F Segura ; Josep Sánchez de Toledo ; Soledad Gallego ; Josep Roma

ITGA9 (integrin, alpha 9)

Atlas Genet Cytogenet Oncol Haematol. 2013-10-01

Online version: http://atlasgeneticsoncology.org/gene/41010/itga9