SPP1

Summary

SPP1 (secreted phosphoprotein 1, HGNC:11255) is a protein-coding gene on chromosome 4q22.1, encoding Osteopontin (P10451). Major non-collagenous bone protein that binds tightly to hydroxyapatite.

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.

Source: NCBI Gene 6696 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus (Supportive, GenCC)
• Clinical variants (ClinVar): 68 total
• Phenotypes (HPO): 80
• Druggable target: yes
• MANE Select transcript: NM_001040058

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11255
Approved symbol	SPP1
Name	secreted phosphoprotein 1
Location	4q22.1
Locus type	gene with protein product
Status	Approved
Aliases	BSPI, ETA-1, lnc-PKD2-2-3
Ensembl gene	ENSG00000118785
Ensembl biotype	protein_coding
OMIM	166490
Entrez	6696

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 14 retained_intron, 13 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000237623, ENST00000360804, ENST00000395080, ENST00000504310, ENST00000505146, ENST00000508002, ENST00000508233, ENST00000509334, ENST00000509659, ENST00000513981, ENST00000614857, ENST00000681973, ENST00000682026, ENST00000682448, ENST00000682554, ENST00000682599, ENST00000682627, ENST00000682655, ENST00000682865, ENST00000683087, ENST00000683168, ENST00000683440, ENST00000683620, ENST00000684106, ENST00000684450, ENST00000684710, ENST00000882522, ENST00000882523, ENST00000882524, ENST00000882525, ENST00000920430, ENST00000942419, ENST00000942420

RefSeq mRNA: 5 — MANE Select: NM_001040058 NM_000582, NM_001040058, NM_001040060, NM_001251829, NM_001251830

CCDS: CCDS34027, CCDS3626, CCDS43250, CCDS93558

Canonical transcript exons

ENST00000395080 — 7 exons

Exon	Start	End
ENSE00002025367	87975714	87975800
ENSE00002033275	87982492	87983411
ENSE00003462002	87981475	87981798
ENSE00003618849	87980046	87980126
ENSE00003629094	87980393	87980434
ENSE00003652331	87977059	87977097
ENSE00003680042	87976882	87976949

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 99.93.

FANTOM5 (CAGE): breadth broad, TPM avg 411.3305 / max 28294.3017, expressed in 906 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
48759	410.6500	904
48760	0.4782	160
48765	0.1645	90
203278	0.0377	4

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	99.93	gold quality
middle frontal gyrus	UBERON:0002702	99.93	gold quality
inferior vagus X ganglion	UBERON:0005363	99.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.85	gold quality
spinal cord	UBERON:0002240	99.83	gold quality
periodontal ligament	UBERON:0008266	99.83	gold quality
subthalamic nucleus	UBERON:0001906	99.79	gold quality
pons	UBERON:0000988	99.78	gold quality
adult mammalian kidney	UBERON:0000082	99.77	gold quality
metanephros cortex	UBERON:0010533	99.77	gold quality
type B pancreatic cell	CL:0000169	99.76	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.74	gold quality
corpus callosum	UBERON:0002336	99.74	gold quality
superior vestibular nucleus	UBERON:0007227	99.74	gold quality
globus pallidus	UBERON:0001875	99.72	gold quality
lateral globus pallidus	UBERON:0002476	99.71	gold quality
tibia	UBERON:0000979	99.70	gold quality
medial globus pallidus	UBERON:0002477	99.70	gold quality
islet of Langerhans	UBERON:0000006	99.69	gold quality
dorsal root ganglion	UBERON:0000044	99.67	gold quality
medulla oblongata	UBERON:0001896	99.67	gold quality
substantia nigra pars compacta	UBERON:0001965	99.66	gold quality
inferior olivary complex	UBERON:0002127	99.56	gold quality
ventral tegmental area	UBERON:0002691	99.56	gold quality
placenta	UBERON:0001987	99.52	gold quality
cranial nerve II	UBERON:0000941	99.51	gold quality
adult organism	UBERON:0007023	99.49	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.47	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.32	gold quality
midbrain	UBERON:0001891	99.28	gold quality

Single-cell (SCXA)

Detected in 44 experiment(s), a significant marker in 42.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	71208.98
E-GEOD-84465	yes	45865.10
E-MTAB-10287	yes	42906.65
E-MTAB-9435	yes	40640.95
E-CURD-112	yes	39835.12
E-GEOD-83139	yes	37999.30
E-HCAD-24	yes	36065.55
E-MTAB-8495	yes	32473.37
E-MTAB-6678	yes	27408.28
E-MTAB-5061	yes	27283.61
E-HCAD-23	yes	19973.25
E-MTAB-9841	yes	17252.30
E-GEOD-137537	yes	15294.70
E-MTAB-10885	yes	13895.62
E-MTAB-10855	yes	13276.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, BMP4, BMP5, BMP6, CEBPA, CEBPB, CREB1, CTNNB1, DLX5, EGR1, ELF1, ELF4, EP300, ERG, ESR1, ESR2, ESRRA, ESRRG, ETS1, ETS2, ETV4, FOS, FOXC1, FOXD3, GLI1, GLI2, GLI3, GLIS3, HAND1, HAND2, HDAC1, HES1, HEY1, HEY2, HIF1A, HNF1A, HNRNPAB, HOXA9, HOXC8

miRNA regulators (miRDB)

46 targeting SPP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-12123	99.52	71.79	2990

Literature-anchored findings (GeneRIF, showing 40)

• upregulated transcripts in brain of patients with multiple sclerosis (PMID:11721059)
• mapping of functional epitopes that are important to cell adhesion and migration (PMID:11787071)
• Increased expression is associated with breast tumor metastasis (PMID:11801541)
• The osteopontin gene, which has a role in immunosurveillance, is a direct target of TP53. (PMID:11807984)
• Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H’s cofactor activity enabling MCP-like cellular evasion of complement-mediated attack. (PMID:11825898)
• OPN induced a profound level of synthesis of IL-12 from noninfected PBMCs. The major cellular source of OPN was monocytes. (PMID:11854181)
• PPARgamma ligands inhibit OPN gene expression through the interference with the binding of nuclear factors to A/T-rich sequence in THP-1 cells. (PMID:11861425)
• an association between levels of a biomarker, osteopontin, and ovarian cancer suggest its clinical usefulness (PMID:11926891)
• Osteopontin modulates prostate carcinoma invasive capacity through RGD-dependent upregulation of plasminogen activators. (PMID:11928818)
• A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with systemic lupus erythematosus (PMID:11933203)
• Osteopontin was suggested to play a role in HCC, especially in cancer-stromal interactions. (PMID:11940202)
• RT-PCR analysis of human bone marrow stromal cells during osteogenesis in vitro: the mRNA levels of bone morphogenetic protein-2 (BMP-2), bone sialoprotein-II (BSP), osteopontin (OP) and cbfa-1 increased with culture time in osteogenic medium. (PMID:11968014)
• has RGD sequence and role in osteoclast adhesion (PMID:11979972)
• Results provide the first evidence that osteopontin may play an important role in stone formation in chronic pancreatitis. (PMID:12142743)
• in human tumor cells, HGF and M-CSF stimulate osteopontin production (which is subsequently used as a substrate for cell adhesion) (PMID:12456016)
• crystal retention in the human kidney may depend on the expression of CD44-, OPN-, and-HA rich cell coats by damaged distal tubular epithelium. (PMID:12506143)
• OPN-induced migration of mammary epithelial cells also requires activation of the EGF pathway. EGF & OPN synergistically induced cell migration. Exogenous OPN increased ligand (TGFalpha> EGF) & EGFR mRNA expression, as well as EGFR kinase activity. (PMID:12606946)
• Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC (PMID:12640447)
• Elevated osteopontin (OPN) transcription often correlates with increased metastatic potential of transformed cells, and in several model systems OPN–whether produced by the tumor cells or by stromal cells - has been shown to enhance metastatic ability. (PMID:12650610)
• osteopontin as the leading candidate clinical marker derived from a screen of approximately 12,000 named genes. (PMID:12650611)
• Association with disease course is detectable in patients with at least one wild-type OPN 1284A allele: these patients are less likely to have a mild disease course and are at increased risk for a secondary-progressive clinical type. (PMID:12761568)
• first report that osteopontin induces nuclear factor kappaB activity and urokinase secretion by activating phosphatidylinositol 3’-kinase/Akt protein/Ikappab kinase-mediated signaling pathways (PMID:12771144)
• study indicates the possibility that osteopontin plays an important role in the pathogenesis of ulcerative colitis via increased immune activity (PMID:12842452)
• OPN expression is significantly higher in malignant epithelial sources over normal and benign epithelial sources, but no difference in expression levels is evident between primary tumors with or without metastases. (PMID:12927044)
• In patients with previous anterior wall myocardial infarction(MI) osteopontin is released from heart into coronary circulation in proportion to left ventricular(LV) systolic function and volumes. Osteopontin may be associated with post-MI LV remodeling. (PMID:12939547)
• OPN binds to the alphavbeta3-integrin to increase plasma membrane CD44v6 expression and augment in vitro adhesion to hyaluronate (PMID:12949055)
• increased expression of the alpha(v)beta(3) integrin during breast cancer progression can make tumor cells more responsive to malignancy-promoting ligands such as OPN and result in increased tumor cell aggressiveness. (PMID:14517343)
• OPN is expressed in breast and prostate cancer and has a role in differentiation and activation of osteoclasts (PMID:14524533)
• platelet adhesion to osteopontin-coated surfaces requires an agonist-induced exposure of alpha v beta 3-binding sites for this ligand (PMID:14534308)
• Opn is among the most abundantly expressed proteins in a range of lung diseases and has been shown to regulate aspects of pulmonary granuloma formation, fibrosis, and malignancy (review) (PMID:14563350)
• Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing Dianzani autoimmune/lymphoproliferative disease than haplotype A homozygotes. (PMID:14592838)
• induces alpha(v)beta(3) integrin-mediated AP-1 activity and urokinase type plasminogen activator secretion by activating c-Src/EGFR/ERK signaling pathways (PMID:14704150)
• OPN promoter region SNP at nt -433 may be a useful marker reflecting hepatitis activity in chronic hepatitis C patients. (PMID:14706653)
• Epidermal growth factor may regulate osteopontin gene expression through PI3K signaling pathway in hepatocellular carcinoma cells (PMID:14716823)
• Nurr1 activates the OPN promoter directly in osteoblastic cells and may have a role in the regulation of bone homeostasis (PMID:14988426)
• Beta-catenin, Lef-1, Ets transcription factors, and the AP-1 protein c-Jun each weakly enhanced luciferase expression from an OPN promoter. (PMID:14990565)
• Notch1 gene expression was decreased 5-fold in osteopontin-treated CD34+ cells (PMID:14996707)
• Myeloma cell lines adhere to OPN, so high stromal OPN expression may be partly responsible for retention of myeloma cells in bone marrow. The high plasma OPN levels may be due to OPN production by tumor cells & tumor-induced production by non-tumor cells. (PMID:15003892)
• The large increase in OPN expression in tumors compared with normal tissue and its association with survival suggest a role for OPN in lung tumorigenesis. (PMID:15014008)
• Osteopontin is expressed at high concentrations in secretory endometrium in epithelial cells and in decidua in stromal cells. Decidual stromal expression of osteopontin is up-regulated by decidualization. (PMID:15019804)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Spp1	ENSMUSG00000029304
rattus_norvegicus	Spp1	ENSRNOG00000043451

Protein

Protein identifiers

Osteopontin — P10451 (reviewed: P10451)

Alternative names: Bone sialoprotein 1, Nephropontin, Secreted phosphoprotein 1, Urinary stone protein, Uropontin

All UniProt accessions (3): P10451, A0A804HLB3, Q3LGB0

UniProt curated annotations — full annotation on UniProt →

Function. Major non-collagenous bone protein that 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.

Subunit / interactions. Interacts (via N-terminus) with integrin ITGA9:ITGB1.

Subcellular location. Secreted.

Tissue specificity. Detected in cerebrospinal fluid and urine (at protein level). Bone. Found in plasma.

Post-translational modifications. Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers, increasing its collagen binding properties. Extensively phosphorylated by FAM20C in the extracellular medium at multiple sites within the S-x-E/pS motif. The phosphorylated form inhibits hydroxyapatite crystallization. Dephosphorylation via a mechanism involving ALPL/TNAP promotes hydroxyapatite crystallization. O-glycosylated. Isoform 5 is GalNAc O-glycosylated at Thr-59 or Ser-62.

Similarity. Belongs to the osteopontin family.

Isoforms (4)

UniProt ID	Names	Canonical?
P10451-1	1, OPN-a, OP1B	yes
P10451-3	3, OPN-c
P10451-4	4
P10451-5	2, OPN-b, OP1A

RefSeq proteins (5): NP_000573, NP_001035147, NP_001035149, NP_001238758, NP_001238759 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002038	Osteopontin	Family
IPR019841	Osteopontin_CS	Conserved_site

Pfam: PF00865

UniProt features (69 total): modified residue 43, glycosylation site 7, compositionally biased region 6, splice variant 3, sequence conflict 3, sequence variant 2, signal peptide 1, chain 1, region of interest 1, short sequence motif 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9EOU	X-RAY DIFFRACTION	1.55
3CXD	X-RAY DIFFRACTION	2.8
3DSF	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10451-F1	53.23	0.00

Antibody-complex structures (SAbDab): 2 — 3CXD, 3DSF

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (43): 24, 26, 27, 62, 63, 66, 76, 78, 81, 99, 102, 105, 108, 117, 120, 123, 126, 129, 185, 190 …

Glycosylation sites (7): 134, 138, 143, 147, 152, 234, 308

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-186797	Signaling by PDGF
R-HSA-216083	Integrin cell surface interactions
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8949275	RUNX3 Regulates Immune Response and Cell Migration
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9856532	Mechanical load activates signaling by PIEZO1 and integrins in osteocytes

MSigDB gene sets: 719 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE45365_NK_CELL_VS_BCELL_UP, MODULE_52, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_COLLATERAL_SPROUTING, TSENG_IRS1_TARGETS_UP, MCLACHLAN_DENTAL_CARIES_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, HARRIS_HYPOXIA, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, ZHAN_MULTIPLE_MYELOMA_MF_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN

GO Biological Process (18): osteoblast differentiation (GO:0001649), androgen catabolic process (GO:0006710), cell adhesion (GO:0007155), embryo implantation (GO:0007566), biomineral tissue development (GO:0031214), response to vitamin D (GO:0033280), response to macrophage colony-stimulating factor (GO:0036005), positive regulation of bone resorption (GO:0045780), positive regulation of DNA-templated transcription (GO:0045893), decidualization (GO:0046697), response to steroid hormone (GO:0048545), negative regulation of collateral sprouting of intact axon in response to injury (GO:0048685), cellular response to testosterone stimulus (GO:0071394), response to 2,3,7,8-tetrachlorodibenzodioxine (GO:1904612), positive regulation of estradiol secretion (GO:2000866), ossification (GO:0001503), signal transduction (GO:0007165), cell differentiation (GO:0030154)

GO Molecular Function (6): cytokine activity (GO:0005125), integrin binding (GO:0005178), calcium ion binding (GO:0005509), small molecule binding (GO:0036094), extracellular matrix binding (GO:0050840), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), cell projection (GO:0042995), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), vesicle (GO:0031982)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Extracellular matrix organization	2
Signaling by Receptor Tyrosine Kinases	1
Metabolism of proteins	1
Transcriptional regulation by RUNX3	1
Post-translational protein modification	1
Cellular responses to mechanical stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
cellular process	2
tissue development	2
response to lipid	2
cytoplasm	2
ossification	1
cell differentiation	1
steroid catabolic process	1
androgen metabolic process	1
hormone catabolic process	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
animal organ development	1
response to vitamin	1
response to oxygen-containing compound	1
response to cytokine	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
maternal placenta development	1
developmental process involved in reproduction	1
response to hormone	1
negative regulation of collateral sprouting	1
collateral sprouting of intact axon in response to injury	1
negative regulation of axon regeneration	1
regulation of collateral sprouting of intact axon in response to injury	1
response to testosterone	1
cellular response to lipid	1
cellular response to ketone	1
response to chemical	1
estradiol secretion	1
positive regulation of steroid hormone secretion	1
regulation of estradiol secretion	1
multicellular organismal process	1
cell communication	1

Protein interactions and networks

STRING

3922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPP1	FN1	P02751	996
SPP1	CD44	P16070	996
SPP1	BGLAP	P02818	994
SPP1	MMP3	P08254	992
SPP1	IBSP	P21815	990
SPP1	ITGAV	P06756	990
SPP1	SPARC	P09486	984
SPP1	GSTM1	P09488	981
SPP1	VTN	P01141	964
SPP1	ITGB1	P05556	950
SPP1	ITGB3	P05106	949
SPP1	AP4M1	O00189	946
SPP1	MMP9	P14780	942
SPP1	MGP	P08493	920
SPP1	DMP1	Q13316	920
SPP1	BMP2	P12643	920

IntAct

45 interactions, top by confidence:

A	B	Type	Score
SPP1	SGTA	psi-mi:“MI:0915”(physical association)	0.830
SGTA	SPP1	psi-mi:“MI:0915”(physical association)	0.830
SPP1	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
FAM20C	SPP1	psi-mi:“MI:0403”(colocalization)	0.640
SPP1	FAM20C	psi-mi:“MI:0915”(physical association)	0.640
SPP1	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
SPP1	SGTB	psi-mi:“MI:0915”(physical association)	0.560
GET3	SPP1	psi-mi:“MI:0915”(physical association)	0.560
SPP1	NCS1	psi-mi:“MI:0915”(physical association)	0.560
BAG6	SPP1	psi-mi:“MI:0915”(physical association)	0.560
CD44	SPP1	psi-mi:“MI:2364”(proximity)	0.510
SPP1	CD44	psi-mi:“MI:2364”(proximity)	0.510
CD44	SPP1	psi-mi:“MI:0403”(colocalization)	0.510
PIK3R1	SPP1	psi-mi:“MI:0915”(physical association)	0.400
SPP1	CCR8	psi-mi:“MI:0915”(physical association)	0.370
SPP1	DRD2	psi-mi:“MI:0915”(physical association)	0.370
SPP1	PTGER4	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	SPP1	psi-mi:“MI:0915”(physical association)	0.370
SPP1	PEPD	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (101): SPP1 (Two-hybrid), SPP1 (Two-hybrid), SPP1 (Two-hybrid), PDLIM7 (Two-hybrid), CTNNBL1 (Two-hybrid), ITGAV (Reconstituted Complex), ITGB1 (Reconstituted Complex), ITGB5 (Reconstituted Complex), F2 (Co-localization), SGTA (Two-hybrid), TRAF3 (Affinity Capture-Western), SPP1 (Affinity Capture-Western), SPP1 (Affinity Capture-MS), SPP1 (Affinity Capture-MS), SPP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A060XQP6, A0A1S4FQ37, A2VD23, A3KQQ9, A7E371, B3A0Q3, B3EWZ0, B3EWZ1, B3EWZ4, B7W112, D1FQ14, E9Q9K5, G5EC21, O01949, O16883, O43493, O46203, O55188, O84462, P08721, P10451, P10923, P13665, P14287, P19814, P23498, P31096, P31097, P31098, P31936, P35662, P35663, P98193, Q13316, Q14093, Q28139, Q5MIT9, Q5SRN2, Q5UQ32, Q62313

Diamond homologs: P08721, P10451, P10923, P14287, P31096, P31097, P31098, Q9XSY9

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
RUNX2	“up-regulates quantity by expression”	SPP1	“transcriptional regulation”
SPP1	“up-regulates activity”	“A9/b1 integrin”	binding
ERG	“up-regulates quantity by expression”	SPP1	“transcriptional regulation”
SMOC1	“up-regulates quantity by expression”	SPP1	“transcriptional regulation”
FAM20C	“down-regulates quantity”	SPP1	phosphorylation
SPP1	up-regulates	“Av/b3 integrin”	binding
RUNX2	“up-regulates quantity”	SPP1	“transcriptional regulation”
ETS2	“up-regulates quantity by expression”	SPP1	“transcriptional regulation”
ALPL	“down-regulates activity”	SPP1	dephosphorylation
DLX5	“up-regulates quantity”	SPP1	“transcriptional regulation”
MMP3	“up-regulates activity”	SPP1	cleavage
MMP7	“up-regulates activity”	SPP1	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

68 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	12
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

668 predictions. Top by Δscore:

Variant	Effect	Δscore
4:87975801:G:GA	donor_loss	1.0000
4:87975802:T:G	donor_loss	1.0000
4:87977049:T:A	acceptor_gain	1.0000
4:87977056:A:AG	acceptor_gain	1.0000
4:87977056:AAG:A	acceptor_gain	1.0000
4:87977057:A:G	acceptor_gain	1.0000
4:87977094:GCAG:G	donor_gain	1.0000
4:87977098:G:GG	donor_gain	1.0000
4:87977098:GTAA:G	donor_loss	1.0000
4:87977848:G:GT	donor_gain	1.0000
4:87980387:CTTCA:C	acceptor_loss	1.0000
4:87980388:TTCA:T	acceptor_loss	1.0000
4:87980389:TCAG:T	acceptor_loss	1.0000
4:87980390:CAGA:C	acceptor_loss	1.0000
4:87980391:A:AG	acceptor_gain	1.0000
4:87980391:A:T	acceptor_loss	1.0000
4:87980392:G:GA	acceptor_gain	1.0000
4:87981466:A:AG	acceptor_gain	1.0000
4:87981467:A:G	acceptor_gain	1.0000
4:87981470:TTCA:T	acceptor_loss	1.0000
4:87981471:TCAG:T	acceptor_loss	1.0000
4:87981472:CAGA:C	acceptor_loss	1.0000
4:87981473:A:AC	acceptor_loss	1.0000
4:87981473:A:AG	acceptor_gain	1.0000
4:87981474:G:GT	acceptor_gain	1.0000
4:87981474:GA:G	acceptor_gain	1.0000
4:87981474:GAC:G	acceptor_gain	1.0000
4:87981474:GACC:G	acceptor_gain	1.0000
4:87981474:GACCC:G	acceptor_gain	1.0000
4:87981740:A:AG	donor_gain	1.0000

AlphaMissense

2148 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:87976920:T:C	C9R	0.977
4:87976914:T:C	C7R	0.965
4:87976929:G:C	G12R	0.950
4:87977080:A:C	S26R	0.931
4:87977082:T:A	S26R	0.931
4:87977082:T:G	S26R	0.931
4:87976930:G:A	G12D	0.924
4:87980081:G:C	W43C	0.916
4:87980081:G:T	W43C	0.916
4:87980079:T:A	W43R	0.915
4:87980079:T:C	W43R	0.915
4:87981734:G:C	R159P	0.899
4:87981736:G:T	G160C	0.897
4:87981739:G:C	D161H	0.890
4:87981736:G:C	G160R	0.884
4:87981740:A:T	D161V	0.882
4:87981737:G:A	G160D	0.873
4:87981740:A:C	D161A	0.870
4:87976924:T:C	L10P	0.862
4:87976924:T:G	L10R	0.860
4:87981737:G:T	G160V	0.848
4:87981741:T:A	D161E	0.845
4:87981741:T:G	D161E	0.845
4:87976906:C:A	A4E	0.838
4:87981740:A:G	D161G	0.821
4:87980105:G:C	K51N	0.806
4:87980105:G:T	K51N	0.806
4:87981644:C:T	S129F	0.805
4:87976922:C:G	C9W	0.792
4:87976924:T:A	L10H	0.792

dbSNP variants (sampled 300 via entrez): RS1000203079 (4:87982283 G>C), RS1000274104 (4:87976190 T>C), RS1000542175 (4:87983794 C>A,T), RS1001010225 (4:87977596 T>A), RS1001531751 (4:87973891 T>C), RS1002863483 (4:87974447 A>G), RS1003025387 (4:87979754 G>A), RS1003060987 (4:87974124 G>C), RS1003915577 (4:87977413 G>A,C), RS1004050688 (4:87983644 T>G), RS1004852860 (4:87974059 T>G), RS1004985115 (4:87979700 C>T), RS1005080487 (4:87980040 T>G), RS1005596763 (4:87975743 G>A,T), RS1005690769 (4:87982552 G>A)

Disease associations

OMIM: gene MIM:166490 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
systemic lupus erythematosus	Supportive	Unknown

Mondo (1): systemic lupus erythematosus (MONDO:0007915)

Orphanet (0):

HPO phenotypes

80 total (30 of 80 shown, HPO-id order):

HPO	Term
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000123	Nephritis
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000707	Abnormality of the nervous system
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000951	Abnormality of the skin
HP:0000969	Edema
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001324	Muscle weakness
HP:0001369	Arthritis
HP:0001541	Ascites
HP:0001596	Alopecia
HP:0001698	Pericardial effusion
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001937	Microangiopathic hemolytic anemia
HP:0001945	Fever
HP:0002013	Vomiting

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741309 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11730582	SPP1		0.00	0

CTD chemical–gene interactions

208 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
sodium arsenite	increases expression	6
Cyclosporine	decreases expression, increases expression	6
Benzo(a)pyrene	increases expression, affects methylation, affects cotreatment, affects expression	5
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, affects expression, increases expression	5
Tretinoin	decreases reaction, increases expression, affects cotreatment	5
methylmercuric chloride	affects cotreatment, increases expression	4
bisphenol A	affects expression, decreases methylation, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression, decreases reaction	4
Quercetin	decreases expression, increases expression	4
Tetradecanoylphorbol Acetate	increases reaction, increases expression, affects cotreatment, affects reaction, affects expression (+2 more)	4
Cadmium Chloride	decreases expression, decreases reaction, increases abundance, increases expression	4
lead acetate	affects reaction, increases expression, increases secretion	3
trichostatin A	affects cotreatment, increases expression	3
(+)-JQ1 compound	decreases expression, affects cotreatment	3
Resveratrol	affects cotreatment, increases expression, decreases reaction	3
Air Pollutants	decreases expression, increases abundance, increases expression, increases secretion	3
Cadmium	increases abundance, increases expression, decreases reaction, decreases expression	3
Calcitriol	affects cotreatment, increases expression	3
Cannabidiol	increases expression	3
Dexamethasone	affects cotreatment, increases expression, decreases reaction	3
Particulate Matter	increases abundance, increases expression, increases secretion, decreases expression	3
naringin	increases expression	2
sulforaphane	increases expression	2
cobaltous chloride	affects reaction, increases expression	2
3,4,5,3’,4’-pentachlorobiphenyl	affects expression, decreases expression	2
beta-glycerophosphoric acid	affects cotreatment, increases expression, decreases reaction	2
mercuric bromide	increases expression, affects cotreatment	2
perfluorooctane sulfonic acid	affects expression, increases expression	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, decreases expression	2

Cellosaurus cell lines

12 cell lines: 12 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A9A7	Hsa/TR/OPN1	Cancer cell line	Sex unspecified
CVCL_A9A8	Hsa/TR/OPN2	Cancer cell line	Sex unspecified
CVCL_B2H8	Abcam HeLa SPP1 KO	Cancer cell line	Female
CVCL_B8Q4	Abcam HCT 116 SPP1 KO	Cancer cell line	Male
CVCL_B9BU	Abcam MCF-7 SPP1 KO	Cancer cell line	Female
CVCL_B9SK	Abcam A-549 SPP1 KO	Cancer cell line	Male
CVCL_E0PW	Ubigene HeLa SPP1 KO	Cancer cell line	Female
CVCL_E1IZ	HyCyte A-549 KO-hSPP1	Cancer cell line	Male
CVCL_TQ22	HAP1 SPP1 (-) 1	Cancer cell line	Male
CVCL_XT79	HAP1 SPP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients