|Location_base_pair||Starts at 88896802 and ends at 88904563 bp from pter ( according to hg19-Feb_2009) [Mapping]|
|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:
- Post-translational modifications:
|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.|
|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.|
|HGNC (Hugo)||SPP1 11255|
|Entrez_Gene (NCBI)||SPP1 6696 secreted phosphoprotein 1|
|Ensembl hg19 (Hinxton)||ENSG00000118785 [Gene_View] chr4:88896802-88904563 [Contig_View] SPP1 [Vega]|
|Ensembl hg38 (Hinxton)||ENSG00000118785 [Gene_View] chr4:88896802-88904563 [Contig_View] SPP1 [Vega]|
|Genomic and cartography|
|GoldenPath hg19 (UCSC)||SPP1 - chr4:88896802-88904563 + 4q22.1 [Description] (hg19-Feb_2009)|
|GoldenPath hg38 (UCSC)||SPP1 - 4q22.1 [Description] (hg38-Dec_2013)|
|Ensembl||SPP1 - 4q22.1 [CytoView hg19] SPP1 - 4q22.1 [CytoView hg38]|
|Mapping of homologs : NCBI||SPP1 [Mapview hg19] SPP1 [Mapview hg38]|
|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 : Unigene||Hs.313 [ NCBI ]|
|Alternative Splicing : Fast-db (Paris)||GSHG0022720|
|Alternative Splicing Gallery||ENSG00000118785|
|Gene Expression||SPP1 [ NCBI-GEO ] SPP1 [ SEEK ] SPP1 [ MEM ]|
|SOURCE (Princeton)||Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]|
|Protein : pattern, domain, 3D structure|
|With graphics : InterPro||P10451|
|Splice isoforms : SwissVar||P10451 (Swissvar)|
|Domaine pattern : Prosite (Expaxy)||OSTEOPONTIN (PS00884)|
|Domains : Interpro (EBI)||Osteopontin Osteopontin_CS|
|Related proteins : CluSTr||P10451|
|Domain families : Pfam (Sanger)||Osteopontin (PF00865)|
|Domain families : Pfam (NCBI)||pfam00865|
|Domain families : Smart (EMBL)||OSTEO (SM00017)|
|DMDM Disease mutations||6696|
|PDB (SRS)||3CXD 3DSF|
|PDB (PDBSum)||3CXD 3DSF|
|PDB (IMB)||3CXD 3DSF|
|PDB (RSDB)||3CXD 3DSF|
|Human Protein Atlas||ENSG00000118785|
|IPI||IPI00021000 IPI00218874 IPI00218875 IPI00385896 IPI00921882 IPI00967067 IPI00306339|
|Protein Interaction databases|
|Ontologies - Pathways|
|Ontology : AmiGO||osteoblast 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-EBI||osteoblast 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 : BIOCARTA||Regulators of Bone Mineralization [Genes]|
|Pathways : KEGG||PI3K-Akt signaling pathway Focal adhesion ECM-receptor interaction Toll-like receptor signaling pathway|
|REACTOME Pathways||REACT_118779 Extracellular matrix organization [pathway]|
|REACTOME Pathways||REACT_111102 Signal Transduction [pathway]|
|Protein Interaction Database||SPP1|
|DoCM (Curated mutations)||SPP1|
|Gene fusion - rearrangements|
|Polymorphisms : SNP, variants|
|NCBI Variation Viewer||SPP1 [hg38]|
|dbSNP Single Nucleotide Polymorphism (NCBI)||SPP1|
|Exome Variant Server||SPP1|
|SNP (GeneSNP Utah)||SPP1|
|SNP : HGBase||SPP1|
|Genetic variants : HAPMAP||SPP1|
|Genomic Variants||SPP1 SPP1 [DGVbeta]|
|ICGC Data Portal||ENSG00000118785|
|Somatic Mutations in Cancer : COSMIC||SPP1|
|CONAN: Copy Number Analysis||SPP1|
|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|
|Impact of mutations||[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor]|
|Mutations and Diseases : HGMD||SPP1|
|Disease Genetic Association||SPP1|
|Huge Navigator||SPP1 [HugePedia] SPP1 [HugeCancerGEM]|
|snp3D : Map Gene to Disease||6696|
|DGIdb (Drug Gene Interaction db)||SPP1|
|Homologs : HomoloGene||SPP1|
|Homology/Alignments : Family Browser (UCSC)||SPP1|
|Phylogenetic Trees/Animal Genes : TreeFam||SPP1|
|Chemical/Protein Interactions : CTD||6696|
|Chemical/Pharm GKB Gene||PA36085|
|Cancer Resource (Charite)||ENSG00000118785|
|PubMed||499 Pubmed reference(s) in Entrez|
|The nature and significance of osteopontin.|
|Connect Tissue Res. 1989;23(2-3):123-36.|
|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.|
|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.|
|Osteopontin: a protein with diverse functions.|
|Denhardt DT, Guo X.|
|FASEB J. 1993 Dec;7(15):1475-82.|
|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.|
|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.|
|The role of osteopontin in tumorigenesis and metastasis.|
|Oates AJ, Barraclough R, Rudland PS.|
|Invasion Metastasis. 1997;17(1):1-15.|
|Osteopontin expression in mammary gland development and tumorigenesis.|
|Rittling SR, Novick KE.|
|Cell Growth Differ. 1997 Oct;8(10):1061-9.|
|Sodek J, Ganss B, McKee MD.|
|Crit Rev Oral Biol Med. 2000;11(3):279-303.|
|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.|
|The metastasis gene osteopontin: a candidate target for cancer therapy.|
|Biochim Biophys Acta. 2001 Dec 28;1552(2):61-85.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|Genetic networks of cooperative redox regulation of osteopontin.|
|Partridge CR, He Q, Brun M, Ramos KS.|
|Matrix Biol. 2008 Jun;27(5):462-74.|
|Osteopontin: regulation in tumor metastasis.|
|Wai PY, Kuo PC.|
|Cancer Metastasis Rev. 2008 Mar;27(1):103-18.|
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|Written||11-2008||Lígia R Rodrigues|
|IBB - Institute for Biotechnology and Bioengineering, Centre of Biological Engineering, Universidade do Minho, 4710-057 Braga, Portugal|
|This paper should be referenced as such :|
|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 : Sun Dec 21 03:04:16 CET 2014|
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