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SPP1 (secreted phosphoprotein 1)

Identity

Other namesBNSP
BSPI
ETA-1
MGC110940
Nephropontin
OPN
SPP-1
Uropontin
osteopontin
HGNC (Hugo) SPP1
LocusID (NCBI) 6696
Location 4q22.1
Location_base_pair Starts at 88896802 and ends at 88904563 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note Gene type: protein coding.

DNA/RNA

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.

Protein

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.
      

    External links

    Nomenclature
    HGNC (Hugo)SPP1   11255
    Cards
    AtlasSPP1ID42379ch4q22
    Entrez_Gene (NCBI)SPP1  6696  secreted phosphoprotein 1
    GeneCards (Weizmann)SPP1
    Ensembl (Hinxton)ENSG00000118785 [Gene_View]  chr4:88896802-88904563 [Contig_View]  SPP1 [Vega]
    ICGC DataPortalENSG00000118785
    AceView (NCBI)SPP1
    Genatlas (Paris)SPP1
    WikiGenes6696
    SOURCE (Princeton)NM_000582 NM_001040058 NM_001040060 NM_001251829 NM_001251830
    Genomic and cartography
    GoldenPath (UCSC)SPP1  -  4q22.1   chr4:88896802-88904563 +  4q22.1   [Description]    (hg19-Feb_2009)
    EnsemblSPP1 - 4q22.1 [CytoView]
    Mapping of homologs : NCBISPP1 [Mapview]
    OMIM166490   
    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)AC_000136 NC_000004 NC_018915 NG_030362 NT_016354 NW_001838915 NW_004929320
    Consensus coding sequences : CCDS (NCBI)SPP1
    Cluster EST : UnigeneHs.313 [ NCBI ]
    CGAP (NCI)Hs.313
    Alternative Splicing : Fast-db (Paris)GSHG0022720
    Alternative Splicing GalleryENSG00000118785
    Gene ExpressionSPP1 [ NCBI-GEO ]     SPP1 [ SEEK ]   SPP1 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP10451 (Uniprot)
    NextProtP10451  [Medical]
    With graphics : InterProP10451
    Splice isoforms : SwissVarP10451 (Swissvar)
    Domaine pattern : Prosite (Expaxy)OSTEOPONTIN (PS00884)   
    Domains : Interpro (EBI)Osteopontin    Osteopontin_CS   
    Related proteins : CluSTrP10451
    Domain families : Pfam (Sanger)Osteopontin (PF00865)   
    Domain families : Pfam (NCBI)pfam00865   
    Domain families : Smart (EMBL)OSTEO (SM00017)  
    DMDM Disease mutations6696
    Blocks (Seattle)P10451
    PDB (SRS)3CXD    3DSF   
    PDB (PDBSum)3CXD    3DSF   
    PDB (IMB)3CXD    3DSF   
    PDB (RSDB)3CXD    3DSF   
    Human Protein AtlasENSG00000118785
    Peptide AtlasP10451
    HPRD01325
    IPIIPI00021000   IPI00218874   IPI00218875   IPI00385896   IPI00921882   IPI00967067   IPI00306339   
    Protein Interaction databases
    DIP (DOE-UCLA)P10451
    IntAct (EBI)P10451
    FunCoupENSG00000118785
    BioGRIDSPP1
    IntegromeDBSPP1
    STRING (EMBL)SPP1
    Ontologies - Pathways
    QuickGOP10451
    Ontology : AmiGOosteoblast differentiation  cytokine activity  protein binding  extracellular region  extracellular space  inflammatory response  cell adhesion  embryo implantation  positive regulation of cell-substrate adhesion  extracellular matrix disassembly  extracellular matrix organization  neutrophil chemotaxis  biomineral tissue development  response to vitamin D  cell projection  apical part of cell  positive regulation of bone resorption  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 vesicular exosome  
    Ontology : EGO-EBIosteoblast differentiation  cytokine activity  protein binding  extracellular region  extracellular space  inflammatory response  cell adhesion  embryo implantation  positive regulation of cell-substrate adhesion  extracellular matrix disassembly  extracellular matrix organization  neutrophil chemotaxis  biomineral tissue development  response to vitamin D  cell projection  apical part of cell  positive regulation of bone resorption  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 vesicular exosome  
    Pathways : BIOCARTARegulators of Bone Mineralization [Genes]   
    Pathways : KEGGPI3K-Akt signaling pathway    Focal adhesion    ECM-receptor interaction    Toll-like receptor signaling pathway   
    REACTOMEP10451 [protein]
    REACTOME PathwaysREACT_118779 Extracellular matrix organization [pathway]
    REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
    Protein Interaction DatabaseSPP1
    Wikipedia pathwaysSPP1
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)SPP1
    SNP (GeneSNP Utah)SPP1
    SNP : HGBaseSPP1
    Genetic variants : HAPMAPSPP1
    1000_GenomesSPP1 
    ICGC programENSG00000118785 
    CONAN: Copy Number AnalysisSPP1 
    Somatic Mutations in Cancer : COSMICSPP1 
    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
    DECIPHER (Syndromes)4:88896802-88904563
    Mutations and Diseases : HGMDSPP1
    OMIM166490   
    MedgenSPP1
    GENETestsSPP1
    Disease Genetic AssociationSPP1
    Huge Navigator SPP1 [HugePedia]  SPP1 [HugeCancerGEM]
    Genomic VariantsSPP1  SPP1 [DGVbeta]
    Exome VariantSPP1
    dbVarSPP1
    ClinVarSPP1
    snp3D : Map Gene to Disease6696
    General knowledge
    Homologs : HomoloGeneSPP1
    Homology/Alignments : Family Browser (UCSC)SPP1
    Phylogenetic Trees/Animal Genes : TreeFamSPP1
    Chemical/Protein Interactions : CTD6696
    Chemical/Pharm GKB GenePA36085
    Clinical trialSPP1
    Cancer Resource (Charite)ENSG00000118785
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineSPP1
    GoPubMedSPP1
    iHOPSPP1

    Bibliography

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    Contributor(s)

    Written11-2008Lígia R Rodrigues
    IBB - Institute for Biotechnology and Bioengineering, Centre of Biological Engineering, Universidade do Minho, 4710-057 Braga, Portugal

    Citation

    This paper should be referenced as such :
    Rodrigues, LR
    SPP1 (secreted phosphoprotein 1)
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(10):733-736.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/SPP1ID42379ch4q22.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Sat Nov 8 16:44:23 CET 2014

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