Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

SPP1 (secreted phosphoprotein 1)

Written2008-11Lígia R Rodrigues
IBB - Institute for Biotechnology, Bioengineering, Centre of Biological Engineering, Universidade do Minho, 4710-057 Braga, Portugal

(Note : for Links provided by Atlas : click)


HGNC (Hugo) SPP1
HGNC Alias symbBSPI
HGNC Alias nameearly T-lymphocyte activation 1
HGNC Previous nameBNSP
HGNC Previous nameosteopontin
 bone sialoprotein I
LocusID (NCBI) 6696
Atlas_Id 42379
Location 4q22.1  [Link to chromosome band 4q22]
Location_base_pair Starts at 87975650 and ends at 87983411 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SPP1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CERS6 (2q24.3) / SPP1 (4q22.1)SPP1 (4q22.1) / ANXA2 (15q22.2)SPP1 (4q22.1) / SPP1 (4q22.1)
Note Gene type: protein coding.


Note Genes encompassed within a 600 kb region on human chromosome 4 encode several noncollageneous bone and dentin proteins. They include osteopontin, bone sialoprotein, dentin matrix protein I, and dentin sialophosphoprotein, all of which have been categorized as members of the small integring-binding ligand N-linked glycoprotein (SIBLING) family-related proteins. The 4 proteins are somewhat similar being secreted, sialylated, phosphorylated, and acidic in nature.
  The gene structure of human osteopontin. Exons are boxed, filled boxes are coding regions and open boxes are untranslated regions.
Description - Osteopontin is encoded by a single copy gene located on the human chromosome 4; 7 exons.
- Codon triplets are not interrupted by introns, and consequently, exon skipping will not affect the codon triplets in the remaining exons.
- The human gene sequence spans ~9 kb and the open reading frame consists of 942 nucleotides from the start codon (in exon 2) to the stop codon (in exon 7).
Transcription - The 5'-untranslated region includes exon 1, which starts a transcription initiation site (AGC).
- The 3'-untranslated region consists of the last part of exon 7, which includes three potential polyadenylation attachment signals (AATAA).
- Exon 2 encodes the signal peptide and the first two amino acids in the mature protein.
- Exon 3 and 5, the two characteristic Ser-Ser-Glu-Glu phosphorylation sequences.
- Exon 4, the two transglutaminase-reactive glutamine residues.
- Exon 6, the aspartic-rich sequence.
- Exon 7 is the largest exon encoding approzimately half of the proteins including the RGD motif and the central thrombin cleavage site.
- There are 3 transcripts for osteopontin splice variants that are OPN-a, OPN-b and OPN-c. Alternative splicing occurs in a region of the molecule that is upstream of the central integrin binding domain and the C-terminal CD44 binding domain. OPN-b lacks exon 5 and OPN-c lacks exon 4.
- Transcriptional regulation is complex and involves multiple pathways including AP-1, Myc, v-Src, RunX/CBF, TGF-B/BMPS/Smad/Hox and Wnt/b-catenin/APC/GSK-3b/Tcf-4.


Note Osteopontin serves as a substrate for thrombin and matrix metalloproteinases (MMP2, MMP3, MMP7, MMP9 and MMP12), can bind to the extracellular matrix proteins fibronectin and collagen, and interacts with integrins alphaV (beta1, beta2 or beta5) and (alpha4, alpha5, alpha8 or alpha9) beta1 surface receptors through an Arg-Gly-Asp (RGD) sequence.
Secreted phosphoprotein 1 (or osteopontin) was identified with 7 protein interactions: ITGAV, IGFBP5, PDLIM7, CD44, ITGA5, CTNNBL1, SGTA.
  Structure of human osteopontin protein indicating selected structural domains.
Description - Recommended name: osteopontin.
- Osteopontin is 314 amino acids in length.
- The molecular weight of osteopontin and associated isoforms are measured between 41 and 75 kDa. Post-translational modifications leading to cell-type and condition-specific variations may account for this variability in molecular weight.
- Osteopontin is extremely hydrophilic with a low isoelectric point (3.5).
- It displays an unusual amino acid composition with 42 serine, 48 aspartic acid and 27 glutaminc acid residues. It is important to notice that 27 out of the 42 serine serine residues are phosphorylated.
- The predicted secondary structure of osteopontin consists of eight alpha-helices and six beta-sheet segments.
- Strutural domains:
  • Aspartate domain - amino acid sequence Asp86-Asp89 - binds hydroxyapatite,
  • RGD sequence - amino acid sequence Arg159-Asp159 - binds alphaVbeta3, alphaVbeta1, alphaVbeta5 and alpha5beta1 integrins,
  • SVVYGLR sequence - amino acid sequence Ser162-Arg168 - binds alpha9beta1 and alpha1beta1 integrins,
  • Thrombin cleavage site - amino acid sequence Arg168-Ser169 - displays RGD sequence,
  • Calcium binding domain - amino acid sequence Asp216-Ser228 - calcium binding,
  • Heparin binding domain - amino acid sequence Asp290-Ile305 - mediates CD44v3 binding.
    - Post-translational modifications:
  • Extensively phosphorylated on clustered serine residues,
  • N- and O-glycosylated.
  • Expression Osteopontin is expressed by cells in a variety of tissues, including bone, dentin, cementum, hypertrophic cartilage, kidney, brain, bone-marrow-derived metrial gland cells, vascular tissues and cytotrophoblasts of the chorionic villus in the uterus and decidua, ganglia of the inner ear, brain cells and specialized epithelia found in mammary, salivary, and sweat glands, in bile and pancreatic ducts, and in distal renal tubules and in the gut, as well as in activated macrophages and lymphocytes.
    Cell types which express osteopontin: osteoclasts, osteoblasts, kidney, breast and skin epithelial cells, nerve cells, vascular smooth muscle cells and endothelial cells. Activated immune cells (T-cells, NK cells, macrophages and Kupfter cells) also express osteopontin.
    Localisation It is predominantly secreted but its intracellular form has also been described.
    Function - Binds tightly to hydroxyapatite. Appears to form an integral part of the mineralized matrix. Probably important to cell-matrix interaction.
    - Acts as a cytokine involved in enhancing production of interferon-gamma and interleukin-12 and reducing production of interleukin-10 and is essential in the pathway that leads to type I immunity.
    - Participates in bone remodelling, inflammation, cancer and immunity to infection disease.
    - Regulates the formation and growth of calcium phosphate and oxalate crystals.
    - Is involved in cell attachment and signalling through integrins.
    - Is involved in cell attachment and signalling through CD44.
    Homology The amino acid sequence of osteopontin is nowadays available for several species, such as rat, mouse, human, pig, rabbit and cow. The referenced mammalian osteopontin sequences are identical in ~33% of the residues, and in addition, many similar amino acids are conserved between the sequences. Identical residues are scattered in clusters. More specifically, the larger clusters are located in the hydrophobic leader sequence (the first 16 residues), in a potential site for N-linked glycosylation, and in several sites for O-linked glycosylation and phosphorylation. A stretch of consecutive aspartic acid residues was also found in all species, as well as a cell attachment RGD motif almost immediately followed by a thrombin cleavage site.

    Implicated in

    Entity Multiple cancers
    Note The ability of osteopontin to interact with a diverse range of factors including cell surface receptors (integrins, CD44), secreted proteases (matrix metalloproteinases, urokinase plasminogen activator) and growth factor/receptor pathways (TGFalpha/EGFR, HGF/MET) is central to its role in malignancy.
    Changes in gene expression implies alterations in cell properties involved in malignancy such as adhesion, migration, invasion, enhanced tumour survival, tumour angiogenesis, and metastasis.
    Disease Multiple cancers such as breast, thyroid, cervical, prostate, lung, gastric, liver and colon.
    At present, it is fully accepted that osteopontin expressed by tumour cells alters their malignant properties, specifically by affecting their ability to grow, invade, and metastatize. However, it is important to notice that osteopontin is expressed both in normal and malignant tissues. Recent studies suggest that osteopontin levels in the blood or tumours of patients with cancer may provide useful clinical information on patient prognoses.
    Prognosis Elevated osteopontin expression correlate with tumour invasion, progression or metastasis in multiple cancers (thyroid, cervical, breast, prostate, lung, gastric, liver and colon). Osteopontin expression is associated with disease progression in patients, with higher levels of osteopontin produced by cancer cells associated with a poorer patient survival.
    Oncogenesis Osteopontin is believed to be an effector of activated oncogenes functioning to facilitate tumour growth and metastasis.


    Utility of osteopontin as a biomarker in recurrent epithelial ovarian cancer.
    Brakora KA, Lee H, Yusuf R, Sullivan L, Harris A, Colella T, Seiden MV.
    Gynecol Oncol. 2004 May;93(2):361-5.
    PMID 15099946
    Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces.
    Brown LF, Berse B, Van de Water L, Papadopoulos-Sergiou A, Perruzzi CA, Manseau EJ, Dvorak HF, Senger DR.
    Mol Biol Cell. 1992 Oct;3(10):1169-80.
    PMID 1421573
    Osteopontin expression and distribution in human carcinomas.
    Brown LF, Papadopoulos-Sergiou A, Berse B, Manseau EJ, Tognazzi K, Perruzzi CA, Dvorak HF, Senger DR.
    Am J Pathol. 1994 Sep;145(3):610-23.
    PMID 8080043
    The nature and significance of osteopontin.
    Butler WT.
    Connect Tissue Res. 1989;23(2-3):123-36.
    PMID 2698313
    Osteopontin promotes vascular endothelial growth factor-dependent breast tumor growth and angiogenesis via autocrine and paracrine mechanisms.
    Chakraborty G, Jain S, Kundu GC.
    Cancer Res. 2008 Jan 1;68(1):152-61.
    PMID 18172307
    Post-translationally modified residues of native human osteopontin are located in clusters: identification of 36 phosphorylation and five O-glycosylation sites and their biological implications.
    Christensen B, Nielsen MS, Haselmann KF, Petersen TE, Sorensen ES.
    Biochem J. 2005 Aug 15;390(Pt 1):285-92.
    PMID 15869464
    Osteopontin: a protein with diverse functions.
    Denhardt DT, Guo X.
    FASEB J. 1993 Dec;7(15):1475-82.
    PMID 8262332
    The functional and clinical roles of osteopontin in cancer and metastasis.
    Furger KA, Menon RK, Tuck AB, Bramwell VH, Chambers AF.
    Curr Mol Med. 2001 Nov;1(5):621-32.
    PMID 11899236
    Downregulation of osteopontin contributes to metastasis suppression by breast cancer metastasis suppressor 1.
    Hedley BD, Welch DR, Allan AL, Al-Katib W, Dales DW, Postenka CO, Casey G, Macdonald IC, Chambers AF.
    Int J Cancer. 2008 Aug 1;123(3):526-34.
    PMID 18470911
    Cloning and characterization of the human osteopontin gene and its promoter.
    Hijiya N, Setoguchi M, Matsuura K, Higuchi Y, Akizuki S, Yamamoto S.
    Biochem J. 1994 Oct 1;303 ( Pt 1):255-62.
    PMID 7945249
    The cDNA and derived amino acid sequence for human osteopontin.
    Kiefer MC, Bauer DM, Barr PJ.
    Nucleic Acids Res. 1989 Apr 25;17(8):3306.
    PMID 2726470
    Osteopontin as a potential diagnostic biomarker for ovarian cancer.
    Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Feltmate CM, Berkowitz RS, Cramer DW, Mok SC.
    JAMA. 2002 Apr 3;287(13):1671-9.
    PMID 11926891
    Osteopontin--a molecule for all seasons.
    Mazzali M, Kipari T, Ophascharoensuk V, Wesson JA, Johnson R, Hughes J.
    QJM. 2002 Jan;95(1):3-13.
    PMID 11834767
    Osteopontin-c is a selective marker of breast cancer.
    Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B, Weber GF.
    Int J Cancer. 2008 Feb 15;122(4):889-97.
    PMID 17960616
    The role of osteopontin in tumorigenesis and metastasis.
    Oates AJ, Barraclough R, Rudland PS.
    Invasion Metastasis. 1997;17(1):1-15.
    PMID 9425320
    Genetic networks of cooperative redox regulation of osteopontin.
    Partridge CR, He Q, Brun M, Ramos KS.
    Matrix Biol. 2008 Jun;27(5):462-74.
    PMID 18378437
    Osteopontin expression in mammary gland development and tumorigenesis.
    Rittling SR, Novick KE.
    Cell Growth Differ. 1997 Oct;8(10):1061-9.
    PMID 9342184
    The role of osteopontin in tumor progression and metastasis in breast cancer.
    Rodrigues LR, Teixeira JA, Schmitt FL, Paulsson M, Lindmark-Mansson H.
    Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1087-97.
    PMID 17548669
    Sodek J, Ganss B, McKee MD.
    Crit Rev Oral Biol Med. 2000;11(3):279-303.
    PMID 11021631
    Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management.
    Tuck AB, Chambers AF, Allan AL.
    J Cell Biochem. 2007 Nov 1;102(4):859-68.
    PMID 17721886
    Osteopontin: regulation in tumor metastasis.
    Wai PY, Kuo PC.
    Cancer Metastasis Rev. 2008 Mar;27(1):103-18.
    PMID 18049863
    The metastasis gene osteopontin: a candidate target for cancer therapy.
    Weber GF.
    Biochim Biophys Acta. 2001 Dec 28;1552(2):61-85.
    PMID 11825687


    This paper should be referenced as such :
    Rodrigues, LR
    SPP1 (secreted phosphoprotein 1)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):733-736.
    Free journal version : [ pdf ]   [ DOI ]

    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
      Dianzani autoimmune lymphoproliferative disease (DALD)

    External links

    HGNC (Hugo)SPP1   11255
    Entrez_Gene (NCBI)SPP1    secreted phosphoprotein 1
    AliasesBNSP; BSPI; ETA-1; OPN
    GeneCards (Weizmann)SPP1
    Ensembl hg19 (Hinxton)ENSG00000118785 [Gene_View]
    Ensembl hg38 (Hinxton)ENSG00000118785 [Gene_View]  ENSG00000118785 [Sequence]  chr4:87975650-87983411 [Contig_View]  SPP1 [Vega]
    ICGC DataPortalENSG00000118785
    TCGA cBioPortalSPP1
    AceView (NCBI)SPP1
    Genatlas (Paris)SPP1
    SOURCE (Princeton)SPP1
    Genetics Home Reference (NIH)SPP1
    Genomic and cartography
    GoldenPath hg38 (UCSC)SPP1  -     chr4:87975650-87983411 +  4q22.1   [Description]    (hg38-Dec_2013)
    GoldenPath hg19 (UCSC)SPP1  -     4q22.1   [Description]    (hg19-Feb_2009)
    GoldenPathSPP1 - 4q22.1 [CytoView hg19]  SPP1 - 4q22.1 [CytoView hg38]
    genome Data Viewer NCBISPP1 [Mapview hg19]  
    Gene and transcription
    Genbank (Entrez)AA665210 AB209987 AB469789 AF052124 AK057738
    RefSeq transcript (Entrez)NM_000582 NM_001040058 NM_001040060 NM_001251829 NM_001251830
    RefSeq genomic (Entrez)
    Consensus coding sequences : CCDS (NCBI)SPP1
    Alternative Splicing GalleryENSG00000118785
    Gene ExpressionSPP1 [ NCBI-GEO ]   SPP1 [ EBI - ARRAY_EXPRESS ]   SPP1 [ SEEK ]   SPP1 [ MEM ]
    Gene Expression Viewer (FireBrowse)SPP1 [ Firebrowse - Broad ]
    GenevisibleExpression of SPP1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)6696
    GTEX Portal (Tissue expression)SPP1
    Human Protein AtlasENSG00000118785-SPP1 [pathology]   [cell]   [tissue]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP10451   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtP10451  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProP10451
    Splice isoforms : SwissVarP10451
    Domaine pattern : Prosite (Expaxy)OSTEOPONTIN (PS00884)   
    Domains : Interpro (EBI)Osteopontin    Osteopontin_CS   
    Domain families : Pfam (Sanger)Osteopontin (PF00865)   
    Domain families : Pfam (NCBI)pfam00865   
    Domain families : Smart (EMBL)OSTEO (SM00017)  
    Conserved Domain (NCBI)SPP1
    Blocks (Seattle)SPP1
    PDB (RSDB)3CXD    3DSF   
    PDB Europe3CXD    3DSF   
    PDB (PDBSum)3CXD    3DSF   
    PDB (IMB)3CXD    3DSF   
    Structural Biology KnowledgeBase3CXD    3DSF   
    SCOP (Structural Classification of Proteins)3CXD    3DSF   
    CATH (Classification of proteins structures)3CXD    3DSF   
    Human Protein Atlas [tissue]ENSG00000118785-SPP1 [tissue]
    Peptide AtlasP10451
    IPIIPI00021000   IPI00218874   IPI00218875   IPI00385896   IPI00921882   IPI00967067   IPI00306339   
    Protein Interaction databases
    DIP (DOE-UCLA)P10451
    IntAct (EBI)P10451
    Ontologies - Pathways
    Ontology : AmiGO"osteoblast differentiation  cytokine activity  integrin binding  protein binding  extracellular region  extracellular space  extracellular space  extracellular space  endoplasmic reticulum lumen  Golgi apparatus  androgen catabolic process  inflammatory response  cell adhesion  cell adhesion  signal transduction  embryo implantation  extracellular matrix organization  biomineral tissue development  response to vitamin D  cell projection  post-translational protein modification  cellular protein metabolic process  positive regulation of bone resorption  positive regulation of transcription, DNA-templated  decidualization  perinuclear region of cytoplasm  response to steroid hormone  negative regulation of collateral sprouting of intact axon in response to injury  extracellular matrix binding  extracellular exosome  cellular response to testosterone stimulus  positive regulation of estradiol secretion"  
    Ontology : EGO-EBI"osteoblast differentiation  cytokine activity  integrin binding  protein binding  extracellular region  extracellular space  extracellular space  extracellular space  endoplasmic reticulum lumen  Golgi apparatus  androgen catabolic process  inflammatory response  cell adhesion  cell adhesion  signal transduction  embryo implantation  extracellular matrix organization  biomineral tissue development  response to vitamin D  cell projection  post-translational protein modification  cellular protein metabolic process  positive regulation of bone resorption  positive regulation of transcription, DNA-templated  decidualization  perinuclear region of cytoplasm  response to steroid hormone  negative regulation of collateral sprouting of intact axon in response to injury  extracellular matrix binding  extracellular exosome  cellular response to testosterone stimulus  positive regulation of estradiol secretion"  
    Pathways : BIOCARTARegulators of Bone Mineralization [Genes]   
    Pathways : KEGGPI3K-Akt signaling pathway    Focal adhesion    ECM-receptor interaction    Toll-like receptor signaling pathway   
    REACTOMEP10451 [protein]
    REACTOME PathwaysR-HSA-8957275 [pathway]   
    NDEx NetworkSPP1
    Atlas of Cancer Signalling NetworkSPP1
    Wikipedia pathwaysSPP1
    Orthology - Evolution
    GeneTree (enSembl)ENSG00000118785
    Phylogenetic Trees/Animal Genes : TreeFamSPP1
    Homologs : HomoloGeneSPP1
    Homology/Alignments : Family Browser (UCSC)SPP1
    Gene fusions - Rearrangements
    Fusion : Fusion_HubBTBD1--SPP1    CAP1--SPP1    CERS6--SPP1    CSH1--SPP1    FTL--SPP1    GFAP--SPP1    GPX3--SPP1    HNRNPL--SPP1    PDIA3--SPP1    PKD2--SPP1    PPT1--SPP1    RP1-309I22.2--SPP1    SEC61A1--SPP1    SPP1--ANXA2    SPP1--BMPR2   
    SPP1--EIF3B    SPP1--FTL    SPP1--MKLN1    SPP1--NPHP3    SPP1--RP1-309I22.2    SPP1--RPS6KC1    SPP1--SLC3A2    SPP1--SPP1    SPP1--ST3GAL1    SPP1--STAT6    SPP1--THSD4    SPP1--TIMP3    SPP1--TYK2    SPP1--UBE2D1   
    Fusion : QuiverSPP1
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerSPP1 [hg38]
    Exome Variant ServerSPP1
    GNOMAD BrowserENSG00000118785
    Varsome BrowserSPP1
    Genomic Variants (DGV)SPP1 [DGVbeta]
    DECIPHERSPP1 [patients]   [syndromes]   [variants]   [genes]  
    CONAN: Copy Number AnalysisSPP1 
    ICGC Data PortalSPP1 
    TCGA Data PortalSPP1 
    Broad Tumor PortalSPP1
    OASIS PortalSPP1 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICSPP1  [overview]  [genome browser]  [tissue]  [distribution]  
    Somatic Mutations in Cancer : COSMIC3DSPP1
    Mutations and Diseases : HGMDSPP1
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch SPP1
    DgiDB (Drug Gene Interaction Database)SPP1
    DoCM (Curated mutations)SPP1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)SPP1 (select a term)
    NCG6 (London) select SPP1
    Cancer3DSPP1(select the gene name)
    Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Genetic Testing Registry SPP1
    NextProtP10451 [Medical]
    Target ValidationSPP1
    Huge Navigator SPP1 [HugePedia]
    Clinical trials, drugs, therapy
    Protein Interactions : CTD
    Pharm GKB GenePA36085
    Clinical trialSPP1
    canSAR (ICR)SPP1 (select the gene name)
    DataMed IndexSPP1
    PubMed499 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Thu Mar 25 20:10:33 CET 2021

    Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

    For comments and suggestions or contributions, please contact us