SPP1 (secreted phosphoprotein 1)

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.

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