1. Gene Aliases

Secreted Phosphoprotein 1, Lnc-PKD2-2-3, Osteopontin, ETA-1, BSPI, BNSP, OPN, Early T-Lymphocyte Activation 1, Urinary Stone Protein, Nephropontin, Uropontin, Early T-Lymphocyte Activation 1, Immunoglobulin Alpha 1 Heavy Chain Constant Region Fusion Protein, Bone Sialoprotein I, SPP1/CALPHA1 Fusion, Bone Sialoprotein 1, SPP-1

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPP1&keywords=spp1]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

androgen catabolic process [The chemical reactions and pathways resulting in the breakdown of androgens, C19 steroid hormones that can stimulate the development of male sexual characteristics. GO:0006710]

bone mineralization [The deposition of hydroxyapatite, a form of calcium phosphate with the formula Ca10(PO4)6(OH)2, in bone tissue. GO:0030282]

calcium ion homeostasis [Any process involved in the maintenance of an internal steady state of calcium ions within an organism or cell. GO:0055074]

cell adhesion [The attachment of a cell, either to another cell or to an underlying substrate such as the extracellular matrix, via cell adhesion molecules. GO:0007155]

cell differentiation [The cellular developmental process in which a relatively unspecialized cell, e.g. embryonic or regenerative cell, acquires specialized structural and/or functional features that characterize a specific cell. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state. GO:0030154]

cellular response to fluid shear stress [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a fluid shear stress stimulus. Fluid shear stress is the force acting on an object in a system where the fluid is moving across a solid surface. GO:0071498]

cellular response to leukemia inhibitory factor [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a leukemia inhibitory factor stimulus. GO:1990830]

cellular response to testosterone stimulus [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a testosterone stimulus. GO:0071394]

collecting duct development [The process whose specific outcome is the progression of a collecting duct over time, from its formation to the mature structure. The collecting duct responds to vasopressin and aldosterone to regulate water, electrolyte and acid-base balance. It is the final common path through which urine flows before entering the ureter and then emptying into the bladder. GO:0072044]

intracellular calcium ion homeostasis [A homeostatic process involved in the maintenance of a steady state level of calcium ions within a cell. GO:0006874]

intracellular chloride ion homeostasis [A homeostatic process involved in the maintenance of a steady state level of chloride ions within a cell. GO:0030644]

intracellular phosphate ion homeostasis [A homeostatic process involved in the maintenance of a steady state level of phosphate ions within a cell. GO:0030643]

intracellular sodium ion homeostasis [A homeostatic process involved in the maintenance of a steady state level of sodium ions within a cell. GO:0006883]

negative regulation of collateral sprouting of intact axon in response to injury [Any process that stops, prevents, or reduces the frequency, rate or extent of collateral sprouting of an intact axon as a result of injury to an axon. GO:0048685]

neutrophil chemotaxis [The directed movement of a neutrophil cell, the most numerous polymorphonuclear leukocyte found in the blood, in response to an external stimulus, usually an infection or wounding. GO:0030593]

ossification [The formation of bone or of a bony substance, or the conversion of fibrous tissue or of cartilage into bone or a bony substance.|Note that this term does not have a 'developmental process' parent because ossification isn't necessarily developmental, can also occur as part of bone remodeling. Instead use 'ossification involved in bone maturation ; GO:0043931'. GO:0001503]

osteoblast differentiation [The process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, a mesodermal or neural crest cell that gives rise to bone. GO:0001649]

positive regulation of DNA-templated transcription [Any process that activates or increases the frequency, rate or extent of cellular DNA-templated transcription. GO:0045893]

positive regulation of bone resorption [Any process that activates or increases the frequency, rate or extent of bone resorption. GO:0045780]

positive regulation of cell-substrate adhesion [Any process that increases the frequency, rate or extent of cell-substrate adhesion. Cell-substrate adhesion is the attachment of a cell to the underlying substrate via adhesion molecules. GO:0010811]

positive regulation of estradiol secretion [Any process that activates or increases the frequency, rate or extent of estradiol secretion. GO:2000866]

response to macrophage colony-stimulating factor [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a macrophage colony-stimulating factor stimulus. GO:0036005]

response to organic substance [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an organic substance stimulus. GO:0010033]

response to steroid hormone [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a steroid hormone stimulus. GO:0048545]

response to vitamin D [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a vitamin D stimulus. GO:0033280]

signal transduction [The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell.|Note that signal transduction is defined broadly to include a ligand interacting with a receptor, downstream signaling steps and a response being triggered. A change in form of the signal in every step is not necessary. Note that in many cases the end of this process is regulation of the initiation of transcription. Note that specific transcription factors may be annotated to this term, but core/general transcription machinery such as RNA polymerase should not. GO:0007165]

urate biosynthetic process [The chemical reactions and pathways resulting in the formation of urate, the anion of uric acid, 2,6,8-trioxypurine. GO:0034418]

MSigDB Signatures:

WP_LUNG_FIBROSIS: Lung fibrosis [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_LUNG_FIBROSIS.html]

WP_COMPLEMENT_SYSTEM: Complement system [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_COMPLEMENT_SYSTEM.html]

WP_TGF_BETA_RECEPTOR_SIGNALING: TGF beta receptor signaling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_TGF_BETA_RECEPTOR_SIGNALING.html]

WP_ENDOCHONDRAL_OSSIFICATION: Endochondral ossification [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_ENDOCHONDRAL_OSSIFICATION.html]

REACTOME_INTEGRIN_CELL_SURFACE_INTERACTIONS: Integrin cell surface interactions [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INTEGRIN_CELL_SURFACE_INTERACTIONS.html]

REACTOME_RUNX3_REGULATES_IMMUNE_RESPONSE_AND_CELL_MIGRATION: RUNX3 Regulates Immune Response and Cell Migration [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_RUNX3_REGULATES_IMMUNE_RESPONSE_AND_CELL_MIGRATION.html]

KEGG_ECM_RECEPTOR_INTERACTION: ECM-receptor interaction [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_ECM_RECEPTOR_INTERACTION.html]

WP_FOCAL_ADHESION: Focal adhesion [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_FOCAL_ADHESION.html]

KEGG_FOCAL_ADHESION: Focal adhesion [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_FOCAL_ADHESION.html]

REACTOME_SIGNALING_BY_PDGF: Signaling by PDGF [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_PDGF.html]

REACTOME_EXTRACELLULAR_MATRIX_ORGANIZATION: Extracellular matrix organization [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_EXTRACELLULAR_MATRIX_ORGANIZATION.html]

REACTOME_DEGRADATION_OF_THE_EXTRACELLULAR_MATRIX: Degradation of the extracellular matrix [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_DEGRADATION_OF_THE_EXTRACELLULAR_MATRIX.html]

REACTOME_SIGNALING_BY_RECEPTOR_TYROSINE_KINASES: Signaling by Receptor Tyrosine Kinases [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_RECEPTOR_TYROSINE_KINASES.html]

WP_PI3K_AKT_SIGNALING_PATHWAY: PI3K Akt signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_PI3K_AKT_SIGNALING_PATHWAY.html]

WP_FOCAL_ADHESION_PI3K_AKT_MTOR_SIGNALING_PATHWAY: Focal adhesion PI3K Akt mTOR signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_FOCAL_ADHESION_PI3K_AKT_MTOR_SIGNALING_PATHWAY.html]

WP_OVERVIEW_OF_PROINFLAMMATORY_AND_PROFIBROTIC_MEDIATORS: Overview of proinflammatory and profibrotic mediators [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_OVERVIEW_OF_PROINFLAMMATORY_AND_PROFIBROTIC_MEDIATORS.html]

REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION: Post-translational protein modification [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION.html]

IBRAHIM_NRF2_UP: Genes up-regulated in HEK293T cells overexpressing FLAG-NRF2 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/IBRAHIM_NRF2_UP.html]

NABA_CORE_MATRISOME: Ensemble of genes encoding core extracellular matrix including ECM glycoproteins, collagens and proteoglycans [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_CORE_MATRISOME.html]

NABA_MATRISOME: Ensemble of genes encoding extracellular matrix and extracellular matrix-associated proteins [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_MATRISOME.html]

WP_OSTEOCLAST_SIGNALING: Osteoclast signaling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_OSTEOCLAST_SIGNALING.html]

WP_OSTEOPONTIN_SIGNALING: Osteopontin signaling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_OSTEOPONTIN_SIGNALING.html]

WP_TYROBP_CAUSAL_NETWORK_IN_MICROGLIA: TYROBP causal network in microglia [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_TYROBP_CAUSAL_NETWORK_IN_MICROGLIA.html]

REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION: RNA Polymerase II Transcription [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_RNA_POLYMERASE_II_TRANSCRIPTION.html]

WP_ROLE_OF_HYPOXIA_ANGIOGENESIS_AND_FGF_PATHWAY_IN_OA_CHONDROCYTE_HYPERTROPHY: Role of hypoxia angiogenesis and FGF pathway in OA chondrocyte hypertrophy [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_ROLE_OF_HYPOXIA_ANGIOGENESIS_AND_FGF_PATHWAY_IN_OA_CHONDROCYTE_HYPERTROPHY.html]

WP_EXTRACELLULAR_VESICLES_IN_THE_CROSSTALK_OF_CARDIAC_CELLS: Extracellular vesicles in the crosstalk of cardiac cells [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_EXTRACELLULAR_VESICLES_IN_THE_CROSSTALK_OF_CARDIAC_CELLS.html]

WP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY: Toll like receptor signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY.html]

KEGG_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY: Toll-like receptor signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene is involved in the attachment of osteoclasts to the mineralized bone matrix. The encoded protein is secreted and binds hydroxyapatite with high affinity. The osteoclast vitronectin receptor is found in the cell membrane and may be involved in the binding to this protein. This protein is also a cytokine that upregulates expression of interferon-gamma and interleukin-12. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GeneCards Summary: SPP1 (Secreted Phosphoprotein 1) is a Protein Coding gene. Diseases associated with SPP1 include Pediatric Systemic Lupus Erythematosus and Dentin Dysplasia. Among its related pathways are Integrin Pathway and ERK Signaling. Gene Ontology (GO) annotations related to this gene include cytokine activity and extracellular matrix binding.

UniProtKB/Swiss-Prot Summary: Specifically dephosphorylates sphingosine 1-phosphate (S1P), dihydro-S1P, and phyto-S1P. Does not act on ceramide 1-phosphate, lysophosphatidic acid or phosphatidic acid [PMID: 16782891]. Sphingosine-1-phosphate phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway [PMID: 12815058, PMID: 11756451, PMID: 16782891]. Regulates the intracellular levels of the bioactive sphingolipid metabolite S1P that regulates diverse biological processes acting both as an extracellular receptor ligand or as an intracellular second messenger [PMID: 11756451, PMID: 12815058, PMID: 16782891]. Involved in efficient ceramide synthesis from exogenous sphingoid bases. Converts S1P to sphingosine, which is readily metabolized to ceramide via ceramide synthase. In concert with sphingosine kinase 2 (SphK2), recycles sphingosine into ceramide through a phosphorylation/dephosphorylation cycle. Regulates endoplasmic-to-Golgi trafficking of ceramides, resulting in the regulation of ceramide levels in the endoplasmic reticulum, preferentially long-chain ceramide species, and influences the anterograde membrane transport of both ceramide and proteins from the endoplasmic reticulum to the Golgi apparatus [PMID: 16782891]. The modulation of intracellular ceramide levels in turn regulates apoptosis. Via S1P levels, modulates resting tone, intracellular Ca(2+) and myogenic vasoconstriction in resistance arteries [PMID: 18583713]. Also involved in unfolded protein response (UPR) and ER stress-induced autophagy via regulation of intracellular S1P levels [PMID: 20798685, PMID: 18583713]. Involved in the regulation of epidermal homeostasis and keratinocyte differentiation.

8. Cellular Location of Gene Product

Cytoplasmic expression in a subset of tissues, most abundant in renal tubules and gallbladder. Positivity in plasma and extracellular matrix. Localized to the Golgi apparatus. Predicted location: Secreted [https://www.proteinatlas.org/ENSG00000118785/subcellular]

9. Mechanistic Information

Summary

Osteopontin (OPN), encoded by the SPP1 gene, functions primarily in cell adhesion, tissue remodeling, and immune response modulation [CS: 10]. It is a major non-collagenous bone protein that binds to hydroxyapatite, suggesting a role in the structural integrity and repair of tissues [CS: 9]. OPN promotes cell attachment and spreading through its RGD (Arg-Gly-Asp) sequence, interacting with integrin receptors [CS: 10]. It also acts as a cytokine, influencing the production of various interleukins and interferon-gamma, thereby playing a crucial role in immune response modulation [CS: 9]. Its involvement in cellular signaling is further evidenced by its ability to bridge two proteins into a biologically active complex [CS: 8].

In lung diseases, the dysregulation of SPP1 is linked to its roles in tissue repair and immune response [CS: 9]. For example, in pulmonary fibrosis, OPN aids in tissue remodeling through processes like epithelial-mesenchymal transition [CS: 8]. In lung cancer, the upregulation of SPP1 may be a response to tissue damage and the need for repair [CS: 7]. However, this upregulation inadvertently supports cancer progression by facilitating cell migration, preventing apoptosis, and promoting tumor cell survival [CS: 8]. Similarly, in response to lung damage from toxins or particulate matter, increased OPN expression can amplify the immune response to clear offending agents [CS: 7]. This includes the potentiation of inflammatory cytokines via pathways like ERK and JNK, highlighting its role in managing the lung's response to injury or stress [CS: 7]. While these responses are integral to tissue repair and defense mechanisms, their dysregulation can contribute to the pathology of lung diseases [CS: 9].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: brain, gallbladder, kidney, placenta (tissue enhanced) [https://www.proteinatlas.org/ENSG00000118785/tissue]

Cell type enchanced: hofbauer cells (cell type enriched) [https://www.proteinatlas.org/ENSG00000118785/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest