SIRPA

Summary

SIRPA (signal regulatory protein alpha, HGNC:9662) is a protein-coding gene on chromosome 20p13, encoding Tyrosine-protein phosphatase non-receptor type substrate 1 (P78324). Immunoglobulin-like cell surface receptor for CD47.

The protein encoded by this gene is a member of the signal-regulatory-protein (SIRP) family, and also belongs to the immunoglobulin superfamily. SIRP family members are receptor-type transmembrane glycoproteins known to be involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. This protein can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and serve as substrates of PTPs. This protein was found to participate in signal transduction mediated by various growth factor receptors. CD47 has been demonstrated to be a ligand for this receptor protein. This gene and its product share very high similarity with several other members of the SIRP family. These related genes are located in close proximity to each other on chromosome 20p13. Multiple alternatively spliced transcript variants have been determined for this gene.

Source: NCBI Gene 140885 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 98 total
• Cancer driver (intOGen): activating (oncogene-like) across 5 cancer types
• MANE Select transcript: NM_001040023

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9662
Approved symbol	SIRPA
Name	signal regulatory protein alpha
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	SHPS1, SIRP, MYD-1, BIT, P84, SHPS-1, SIRPalpha, CD172a, SIRPalpha2, MFR, SIRP-ALPHA-1
Ensembl gene	ENSG00000198053
Ensembl biotype	protein_coding
OMIM	602461
Entrez	140885

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 40 protein_coding

ENST00000356025, ENST00000358771, ENST00000400068, ENST00000622179, ENST00000889442, ENST00000889443, ENST00000889444, ENST00000889445, ENST00000889446, ENST00000889447, ENST00000889448, ENST00000889449, ENST00000889450, ENST00000889451, ENST00000889452, ENST00000889453, ENST00000889454, ENST00000889455, ENST00000889456, ENST00000889457, ENST00000889458, ENST00000889459, ENST00000889460, ENST00000889461, ENST00000889462, ENST00000889463, ENST00000889464, ENST00000889465, ENST00000889466, ENST00000889467, ENST00000889468, ENST00000889469, ENST00000913920, ENST00000913921, ENST00000913922, ENST00000964293, ENST00000964294, ENST00000964295, ENST00000964296, ENST00000964297

RefSeq mRNA: 4 — MANE Select: NM_001040023 NM_001040022, NM_001040023, NM_001330728, NM_080792

CCDS: CCDS13022, CCDS82593

Canonical transcript exons

ENST00000358771 — 8 exons

Exon	Start	End
ENSE00000655714	1924764	1924877
ENSE00000655716	1934715	1934754
ENSE00001043117	1927875	1927899
ENSE00001290620	1895407	1895526
ENSE00001673100	1915099	1915455
ENSE00001735773	1922313	1922645
ENSE00001805661	1921395	1921712
ENSE00003740022	1937320	1940592

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 98.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.8965 / max 597.0157, expressed in 1634 samples.

FANTOM5 promoters (21 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183122	20.2146	1381
183115	7.5298	1424
183106	4.3012	754
183116	3.6511	1155
183119	2.5075	715
183113	1.7975	853
183114	1.6305	795
183111	1.4506	528
183126	1.0236	460
183117	0.4599	242

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.50	gold quality
postcentral gyrus	UBERON:0002581	97.27	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.24	gold quality
cerebellar hemisphere	UBERON:0002245	97.16	gold quality
prefrontal cortex	UBERON:0000451	97.13	gold quality
cerebellar cortex	UBERON:0002129	97.09	gold quality
superior frontal gyrus	UBERON:0002661	96.98	gold quality
parietal lobe	UBERON:0001872	96.94	gold quality
amygdala	UBERON:0001876	96.94	gold quality
middle temporal gyrus	UBERON:0002771	96.77	gold quality
nucleus accumbens	UBERON:0001882	96.64	gold quality
caudate nucleus	UBERON:0001873	96.56	gold quality
lateral globus pallidus	UBERON:0002476	96.50	gold quality
monocyte	CL:0000576	96.46	gold quality
temporal lobe	UBERON:0001871	96.46	gold quality
cerebellum	UBERON:0002037	96.41	gold quality
mononuclear cell	CL:0000842	96.33	gold quality
cingulate cortex	UBERON:0003027	96.29	gold quality
leukocyte	CL:0000738	96.28	gold quality
Ammon’s horn	UBERON:0001954	96.19	gold quality
anterior cingulate cortex	UBERON:0009835	96.11	gold quality
putamen	UBERON:0001874	96.09	gold quality
entorhinal cortex	UBERON:0002728	95.86	gold quality
frontal cortex	UBERON:0001870	95.85	gold quality
telencephalon	UBERON:0001893	95.73	gold quality
cerebral cortex	UBERON:0000956	95.50	gold quality
orbitofrontal cortex	UBERON:0004167	95.34	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.12
E-MTAB-6678	yes	10.55
E-MTAB-5061	no	3.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
IL12RB1	Unknown
IL12RB2	Unknown

Upstream regulators (CollecTRI, top): E2F4, STAT2

miRNA regulators (miRDB)

126 targeting SIRPA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-106A-5P	99.90	73.94	2683

Literature-anchored findings (GeneRIF, showing 40)

• Signal regulatory protein (SIRPalpha), a cellular ligand for CD47, regulates neutrophil transmigration (PMID:11792697)
• The interaction of SHPS-1 with CD47 may contribute to the recruitment of B lymphocytes via endothelial cells under steady state conditions. (PMID:11907074)
• MyD-1-coupling to this PI 3-kinase-dependent signaling pathway may therefore present a novel target for the development of therapeutic strategies for combating TNFalpha production and consequent inflammatory disease. (PMID:12805067)
• Expression of SIRPalpha1 on astrocytomas may be of considerable importance in brain tumor biology. (PMID:14729615)
• Review. The interaction between CD47 and SIRPalpha seems to be important to limit destruction of host cells in autoimmune diseases like autoimmune hemolytic anemia (AIHA), where macrophages destroy antibody or complement opsonized cells. (PMID:15359629)
• Down-modulation of EGFR signaling leads to transcriptional up-regulation of the inhibitory SIRPalpha1 gene. (PMID:15374953)
• SHPS-1 negatively regulates platelet function via CD47, especially alpha(IIb)beta(3)-mediated outside-in signaling (PMID:15842360)
• SHPS-1 functions as an anchor protein that recruits both Shc and SHP-2, whose recruitment is necessary for IGF-I-dependent Shc phosphorylation (PMID:15888547)
• SIRPalpha-CD47 interactions, which reportedly define self, exhibit cell type specificity and limited cross-species reactivity (PMID:16291597)
• highlight major species differences in CD47-SIRPalpha interactions and CD47 integration, suggesting that signaling by CD47 in man may be qualitatively different from mouse. (PMID:16697668)
• Upon IGF-I stimulation, a complex assembles on SHPS-1 that contains SHP-2, c-Src, and Shc wherein Src phosphorylates Shc, a signaling step that is necessary for an optimal mitogenic response (PMID:16825188)
• These results thus revealed the molecular basis by which SIRPalpha binds to CD47 and shed new light into the structural mechanisms of SIRP isoform mediated distinctive extracellular interactions and cellular responses. (PMID:17070842)
• analysis of species-specific CD47 interactions with signal regulatory protein alpha (PMID:17098740)
• the SIRP-alpha pathway might be part of the molecular machinery used by the DC to dampen or resolve an inflammatory response in an IL-10-independent manner (PMID:17142753)
• Relationship between ATM kinase and extracellular signal-regulated kinase 1/2 (ERK1/2), a key mitogenic stimulator. (PMID:17178844)
• Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPalpha on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection. (PMID:17360380)
• Forced expression of either SIRPalpha1 or SIRPalpha2 displayed distinct suppressive effect on the anchorage-independent growth of Hs578T breast carcinoma cells. (PMID:17632076)
• SIRPalpha may accomplish innate immune activation by seqeuestration of lipopolysaccharides and may modulate toll-like receptor signaling. (PMID:17954568)
• a specific functional role for SIRPalpha in chondrocyte mechano-transduction. (PMID:18051954)
• Data show that forced expression in muscle of the Shp2-activator SIRPalpha1 enhances the disassembly of AChR clusters, whereas the expression of a truncated SIRPalpha1 mutant that suppresses Shp2 signaling inhibites cluster disassembly. (PMID:18647419)
• SIRPalpha negatively regulates beta(2) integrin-mediated monocyte adhesion, transendothelial migration and phagocytosis (PMID:18820737)
• In this review, the CD47/thrombospondin-1/signal-regulatory protein (SIRP)-alpha inhibitory axis is proposed as an important sensor to maintain homeostasis and regulate innate and adaptive immune responses. (PMID:18855618)
• Expression levels of CD47, CD35, CD55, and CD59 on red blood cells and signal-regulatory protein-alpha,beta on monocytes from patients with warm autoimmune hemolytic anemia. (PMID:18954403)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Data emphasize the importance of formation of SHPS-1 signaling complex induced by IGF-I and provide novel insights into our knowledge of the role of this molecular scaffold in regulation of IGF-I-stimulated signal transduction and biological actions. (PMID:19299420)
• Data show show that the CD47-SIRPalpha interaction will span a distance of around 14 nm between interacting cells, comparable with that of an immunological synapse. (PMID:19628875)
• CD47/SIRP-alpha interactions are implicated in the pathogenesis of DC-driven allergic airway inflammation. (PMID:19748659)
• SIRP alpha gene expression is higher in monocytes from autoimmune hemolytic anemia patients, compared with basal expression. (PMID:19874234)
• Insulin-like growth factor-I-stimulated insulin receptor substrate-1 negatively regulates Src homology 2 domain-containing protein-tyrosine phosphatase substrate-1 function in vascular smooth muscle cells. (PMID:20207740)
• Inhibition of engulfment correlates with affinity of CD47 for SIRPA - but only at low levels of CD47. (PMID:20299253)
• SIRPalpha1 specifically affects the SHP-2/FAK/Grb2/Sos-1/MAPK activation loop to downmodulate EGFRvIII-mediated migration and transformation. (PMID:20473329)
• Findings reveal a novel mechanism for recruitment of PDK1 to the SHPS-1 signaling complex, which is required for IGF-I-stimulated AKT Thr(308) phosphorylation and inhibition of apoptosis. (PMID:20643654)
• Poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells. (PMID:20705613)
• The prolactin receptor (PRLr)-SIRPalpha-integrin complex provides a basis for integrin-PRLr cross-talk that contributes to the biology of breast cancer. (PMID:20826546)
• The role of cis dimerization of signal regulatory protein alpha (SIRPalpha) in binding to CD47. (PMID:20826801)
• SHP-2 as an essential component of tumor suppression and anoikis mediated by SIRPalpha1 in human breast carcinoma cells as well as in v-Src-transformed cells. (PMID:21169408)
• Single Nucleotide Polymorphisms in PTPNS1 is associated with inflammatory bowel disease. (PMID:21225905)
• the relationships between SIRPalpha1 and beta-catenin in leukemia cells. (PMID:21369691)
• Sensing of cell surface CD47 expression by phagocyte SIRPalpha is a critical determinant of T- and natural killer-cell homeostasis under steady-state conditions in vivo. (PMID:21788504)
• hSIRPa-transgenic Rag2(-/-)gamma(c)(-/-) mice represent a unique mouse strain supporting high levels of human cell engraftment. (PMID:21788509)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sirpa	ENSMUSG00000037902
mus_musculus	Sirpb1c	ENSMUSG00000074677
mus_musculus	Gm5150	ENSMUSG00000078780
mus_musculus	Sirpd	ENSMUSG00000078783
mus_musculus	Sirpb1b	ENSMUSG00000095028
mus_musculus	Sirpb1a	ENSMUSG00000095788
rattus_norvegicus	Sirpa	ENSRNOG00000004763
rattus_norvegicus	LOC100909964	ENSRNOG00000043478
rattus_norvegicus	AABR07008876.1	ENSRNOG00000053292

Paralogs (4): SIRPG (ENSG00000089012), SIRPB1 (ENSG00000101307), SIRPD (ENSG00000125900), SIRPB2 (ENSG00000196209)

Protein

Protein identifiers

Tyrosine-protein phosphatase non-receptor type substrate 1 — P78324 (reviewed: P78324)

Alternative names: Brain Ig-like molecule with tyrosine-based activation motifs, CD172 antigen-like family member A, Inhibitory receptor SHPS-1, Macrophage fusion receptor, MyD-1 antigen, Signal-regulatory protein alpha-1, Signal-regulatory protein alpha-2, Signal-regulatory protein alpha-3, p84

All UniProt accessions (2): B4DP97, P78324

UniProt curated annotations — full annotation on UniProt →

Function. Immunoglobulin-like cell surface receptor for CD47. Acts as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane. Supports adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment. May play a key role in intracellular signaling during synaptogenesis and in synaptic function. Involved in the negative regulation of receptor tyrosine kinase-coupled cellular responses induced by cell adhesion, growth factors or insulin. Mediates negative regulation of phagocytosis, mast cell activation and dendritic cell activation. CD47 binding prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Plays a role in antiviral immunity and limits new world arenavirus infection by decreasing virus internalization. Receptor for THBS1. Interaction with THBS1 stimulates phosphorylation of SIRPA. In response to THBS1, involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production.

Subunit / interactions. Binds PTPN11 when tyrosine-phosphorylated, except in macrophages, where it primarily binds PTPN6. Binds GRB2 in vitro. Binds FGR. Binds JAK2 irrespective of its phosphorylation status and forms a stable complex. Binds SCAP1 and/or SCAP2. The resulting complex recruits FYB1. Binds PTK2B. Interacts with TRIM2.

Subcellular location. Membrane.

Tissue specificity. Ubiquitous. Highly expressed in brain. Detected on myeloid cells, but not T-cells. Detected at lower levels in heart, placenta, lung, testis, ovary, colon, liver, small intestine, prostate, spleen, kidney, skeletal muscle and pancreas.

Post-translational modifications. N-glycosylated. Phosphorylated on tyrosine residues in response to stimulation with EGF, growth hormone, insulin and PDGF. Dephosphorylated by PTPN11.

Isoforms (3)

UniProt ID	Names	Canonical?
P78324-1	1	yes
P78324-2	2
P78324-4	4

RefSeq proteins (4): NP_001035111, NP_001035112, NP_001317657, NP_542970 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003597	Ig_C1-set	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051755	Ig-like_CS_Receptor	Family

Pfam: PF07654, PF07686

UniProt features (108 total): sequence variant 46, strand 26, short sequence motif 5, modified residue 4, glycosylation site 4, helix 3, compositionally biased region 3, disulfide bond 3, domain 3, topological domain 2, splice variant 2, sequence conflict 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
9TF5	X-RAY DIFFRACTION	1.63
2UV3	X-RAY DIFFRACTION	1.8
6NMT	X-RAY DIFFRACTION	1.83
2JJS	X-RAY DIFFRACTION	1.85
4CMM	X-RAY DIFFRACTION	1.92
6NMS	X-RAY DIFFRACTION	2.11
6BIT	X-RAY DIFFRACTION	2.19
7ST5	X-RAY DIFFRACTION	2.2
7KPG	X-RAY DIFFRACTION	2.27
2JJT	X-RAY DIFFRACTION	2.3
6NMR	X-RAY DIFFRACTION	2.42
2WNG	X-RAY DIFFRACTION	2.49
6NMU	X-RAY DIFFRACTION	2.55
6NMV	X-RAY DIFFRACTION	2.61
7YGG	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78324-F1	78.15	0.55

Antibody-complex structures (SAbDab): 8 — 6BIT, 6NMR, 6NMS, 6NMT, 6NMU, 6NMV, 7KPG, 7ST5

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 (4): 429, 453, 470, 496

Disulfide bonds (3): 55–121, 170–228, 273–331

Glycosylation sites (4): 245, 270, 292, 319

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-391160	Signal regulatory protein family interactions
R-HSA-6798695	Neutrophil degranulation
R-HSA-109582	Hemostasis
R-HSA-1500931	Cell-Cell communication
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 418 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_SECRETORY_GRANULE, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (31): cell adhesion (GO:0007155), regulation of gene expression (GO:0010468), cell migration (GO:0016477), negative regulation of lipopolysaccharide-mediated signaling pathway (GO:0031665), regulation of type II interferon production (GO:0032649), regulation of interleukin-1 beta production (GO:0032651), regulation of interleukin-6 production (GO:0032675), regulation of tumor necrosis factor production (GO:0032680), negative regulation of interferon-beta production (GO:0032688), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), monocyte extravasation (GO:0035696), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), negative regulation of nitric oxide biosynthetic process (GO:0045019), regulation of nitric oxide biosynthetic process (GO:0045428), negative regulation of JNK cascade (GO:0046329), negative regulation of inflammatory response (GO:0050728), negative regulation of phagocytosis (GO:0050765), positive regulation of phagocytosis (GO:0050766), positive regulation of T cell activation (GO:0050870), cellular response to hydrogen peroxide (GO:0070301), negative regulation of ERK1 and ERK2 cascade (GO:0070373), cellular response to type II interferon (GO:0071346), cellular response to interleukin-1 (GO:0071347), cellular response to interleukin-12 (GO:0071349), negative regulation of macrophage inflammatory protein 1 alpha production (GO:0071641), negative regulation of chemokine (C-C motif) ligand 5 production (GO:0071650), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of reactive oxygen species metabolic process (GO:2000379), heterotypic cell-cell adhesion (GO:0034113), cell-cell adhesion (GO:0098609)

GO Molecular Function (9): protein phosphatase inhibitor activity (GO:0004864), SH3 domain binding (GO:0017124), protein phosphatase binding (GO:0019903), GTPase regulator activity (GO:0030695), protein binding involved in heterotypic cell-cell adhesion (GO:0086080), cell-cell adhesion mediator activity (GO:0098632), protein antigen binding (GO:1990405), protein tyrosine kinase binding (GO:1990782), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Hemostasis	1
Cell-Cell communication	1
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of response to external stimulus	2
regulation of cytokine production	2
interleukin-6 production	2
tumor necrosis factor production	2
nitric oxide biosynthetic process	2
phagocytosis	2
regulation of phagocytosis	2
cellular anatomical structure	2
secretory granule membrane	2
tertiary granule	2
cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cell motility	1
negative regulation of response to biotic stimulus	1
negative regulation of signal transduction	1
lipopolysaccharide-mediated signaling pathway	1
regulation of lipopolysaccharide-mediated signaling pathway	1
type II interferon production	1
interleukin-1 beta production	1
regulation of interleukin-1 production	1
regulation of tumor necrosis factor superfamily cytokine production	1
negative regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
negative regulation of cytokine production	1
regulation of interleukin-6 production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
cellular extravasation	1
mononuclear cell migration	1
myeloid leukocyte migration	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
regulation of biosynthetic process	1
regulation of nitric oxide metabolic process	1
JNK cascade	1

Protein interactions and networks

STRING

2605 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIRPA	CD47	Q08722	999
SIRPA	PTPN11	Q06124	997
SIRPA	CD200	P41217	983
SIRPA	SFTPD	P35247	936
SIRPA	CD24	P25063	880
SIRPA	CD200R1	Q8TD46	861
SIRPA	CD274	Q9NZQ7	826
SIRPA	MPZL1	O95297	818
SIRPA	CALR	P27797	816
SIRPA	CX3CR1	P49238	787
SIRPA	LRP1	Q07954	749
SIRPA	PTPRC	P08575	749
SIRPA	CD36	P16671	727
SIRPA	THBS1	P07996	721
SIRPA	CSF1	P09603	718

IntAct

22 interactions, top by confidence:

A	B	Type	Score
PTPN11	GRB2	psi-mi:“MI:0914”(association)	0.910
SIRPA	CD47	psi-mi:“MI:0407”(direct interaction)	0.790
CD47	SIRPA	psi-mi:“MI:0915”(physical association)	0.790
CD47	SIRPA	psi-mi:“MI:0407”(direct interaction)	0.790
PTPN11	SIRPA	psi-mi:“MI:0914”(association)	0.530
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
CLEC4A	SEMA7A	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
INPP5D	SIRPA	psi-mi:“MI:0407”(direct interaction)	0.440
SIRPG	SIRPA	psi-mi:“MI:0915”(physical association)	0.400
NOL3	SIRPA	psi-mi:“MI:0915”(physical association)	0.370
TRIM2	SIRPA	psi-mi:“MI:0915”(physical association)	0.370
PTPN6	SIRPA	psi-mi:“MI:0915”(physical association)	0.370
PB2		psi-mi:“MI:0914”(association)	0.350
CLEC4A	RBFOX3	psi-mi:“MI:0914”(association)	0.350
SIRPA	SIRPB1	psi-mi:“MI:0914”(association)	0.350
SH2D1B	ABLIM1	psi-mi:“MI:0914”(association)	0.350
CLEC4A		psi-mi:“MI:0914”(association)	0.350
HTT	TPP1	psi-mi:“MI:0914”(association)	0.350
KRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
HRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (165): SIRPA (Two-hybrid), SIRPA (Two-hybrid), SIRPA (Two-hybrid), SIRPA (Two-hybrid), SIRPA (Two-hybrid), CCDC57 (Two-hybrid), SIRPA (Affinity Capture-MS), SIRPA (Two-hybrid), SIRPA (Two-hybrid), SIRPA (Affinity Capture-Western), SIRPA (Proximity Label-MS), SIRPA (Affinity Capture-MS), SIRPA (Affinity Capture-Western), SIRPA (Affinity Capture-MS), MATK (Two-hybrid)

ESM2 similar proteins: A8MVW5, B0CLX4, D3YX43, O00241, O46631, O54901, P01854, P01874, P01877, P01880, P04218, P05540, P0C788, P0DOX3, P0DOX4, P16003, P16004, P20273, P23086, P23088, P33705, P35329, P41217, P43121, P43303, P46630, P51866, P78324, P79184, P79185, P97710, P97797, Q08338, Q08340, Q15109, Q28173, Q29037, Q5FWR8, Q5JXA9, Q5TFQ8

Diamond homologs: O00241, O46631, P01691, P01844, P01845, P01847, P01915, P04230, P04231, P18211, P18468, P18469, P18470, P20040, P78324, P97710, P97797, Q5JXA9, Q5TFQ8, Q9H106, Q9P1W8, Q9PWR4, P55899, Q29980, C1ITJ8, O19477, O35799, O73895, P01870, P01889, P01893, P01894, P01895, P01896, P01897, P01898, P01899, P01900, P01901, P01902

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IGF1R	up-regulates	SIRPA

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signal regulatory protein family interactions	6	212.1×	2e-11
Signaling by FLT3 ITD and TKD mutants	5	200.3×	2e-09
Tie2 Signaling	5	158.2×	4e-09
FRS-mediated FGFR3 signaling	5	143.1×	6e-09
FRS-mediated FGFR4 signaling	5	130.7×	8e-09
FRS-mediated FGFR1 signaling	5	120.2×	1e-08
FRS-mediated FGFR2 signaling	5	115.6×	1e-08
Downstream signal transduction	5	100.2×	2e-08

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 5 cancer types — AML, CESC, COADREAD, HGGNOS, MLYM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	68
Likely benign	13
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2031 predictions. Top by Δscore:

Variant	Effect	Δscore
20:1915451:GCGCG:G	donor_gain	1.0000
20:1915452:CGCGG:C	donor_loss	1.0000
20:1915456:G:GA	donor_loss	1.0000
20:1915457:T:A	donor_loss	1.0000
20:1937312:A:AG	acceptor_gain	1.0000
20:1937315:TCCAG:T	acceptor_loss	1.0000
20:1937317:CAGGA:C	acceptor_loss	1.0000
20:1937318:AGGAC:A	acceptor_loss	1.0000
20:1894392:G:GT	donor_gain	0.9900
20:1894839:G:GT	donor_gain	0.9900
20:1894839:G:T	donor_gain	0.9900
20:1895435:GCA:G	acceptor_loss	0.9900
20:1895436:CAGC:C	acceptor_loss	0.9900
20:1895437:A:AG	acceptor_gain	0.9900
20:1895437:A:AT	acceptor_loss	0.9900
20:1895437:AGCC:A	acceptor_gain	0.9900
20:1895438:G:C	acceptor_loss	0.9900
20:1895438:G:GA	acceptor_gain	0.9900
20:1895438:GC:G	acceptor_gain	0.9900
20:1895438:GCC:G	acceptor_gain	0.9900
20:1895438:GCCG:G	acceptor_gain	0.9900
20:1895438:GCCGC:G	acceptor_gain	0.9900
20:1895522:GTCAG:G	donor_gain	0.9900
20:1895527:G:GG	donor_gain	0.9900
20:1915453:GCG:G	donor_gain	0.9900
20:1915456:G:GG	donor_gain	0.9900
20:1915458:GA:G	donor_loss	0.9900
20:1915459:AGTA:A	donor_loss	0.9900
20:1924754:T:TA	acceptor_gain	0.9900
20:1924762:A:AG	acceptor_gain	0.9900

AlphaMissense

3258 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:1915221:T:A	W68R	0.989
20:1915221:T:C	W68R	0.989
20:1915223:G:C	W68C	0.987
20:1915223:G:T	W68C	0.987
20:1915182:T:A	C55S	0.983
20:1915183:G:C	C55S	0.983
20:1921508:T:A	W184R	0.981
20:1921508:T:C	W184R	0.981
20:1924814:T:C	C380R	0.981
20:1921481:T:C	F175L	0.980
20:1921483:C:A	F175L	0.980
20:1921483:C:G	F175L	0.980
20:1922390:T:C	F278L	0.979
20:1922392:C:A	F278L	0.979
20:1922392:C:G	F278L	0.979
20:1915182:T:C	C55R	0.974
20:1915380:T:A	C121S	0.974
20:1915381:G:C	C121S	0.974
20:1915374:T:G	Y119D	0.973
20:1937539:T:C	Y496H	0.973
20:1937549:T:A	V499D	0.969
20:1915380:T:C	C121R	0.967
20:1915184:C:G	C55W	0.960
20:1937543:C:A	A497D	0.959
20:1915381:G:A	C121Y	0.957
20:1915222:G:C	W68S	0.956
20:1921510:G:C	W184C	0.956
20:1921510:G:T	W184C	0.956
20:1922375:T:C	C273R	0.956
20:1915382:T:G	C121W	0.954

dbSNP variants (sampled 300 via entrez): RS1000154217 (20:1897439 A>G), RS1000207828 (20:1897205 A>G), RS1000211340 (20:1936261 T>C,G), RS1000309633 (20:1904387 C>T), RS1000406018 (20:1907834 G>A), RS1000502774 (20:1940162 A>T), RS1000540250 (20:1896096 C>A,G), RS1000615127 (20:1920733 T>C), RS1000618862 (20:1939950 G>T), RS1000626073 (20:1906864 T>C), RS1000671410 (20:1914974 A>C,G), RS1000686790 (20:1902450 C>T), RS1000881571 (20:1931608 G>A,C), RS1000884032 (20:1894614 G>A), RS1000914952 (20:1894815 C>A,T)

Disease associations

OMIM: gene MIM:602461 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000497_14	Mean platelet volume	8.000000e-11
GCST000943_7	Aortic root size	3.000000e-08
GCST001335_3	Mean platelet volume	6.000000e-14
GCST002207_7	Liver enzyme levels (alanine transaminase)	5.000000e-06
GCST004599_207	Mean platelet volume	9.000000e-69
GCST004634_15	Basophil percentage of granulocytes	4.000000e-11
GCST005991_48	Platelet count	4.000000e-25
GCST006585_435	Blood protein levels	0.000000e+00
GCST90002385_521	High light scatter reticulocyte count	5.000000e-16
GCST90002395_588	Mean platelet volume	2.000000e-195
GCST90002401_306	Platelet distribution width	4.000000e-14
GCST90002405_436	Reticulocyte count	4.000000e-13
GCST90002406_539	Reticulocyte fraction of red cells	3.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007995	basophil percentage of granulocytes
EFO:0004309	platelet count
EFO:0007986	reticulocyte count
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs191934521	SIRPA		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, affects cotreatment, increases expression	3
Tetrachlorodibenzodioxin	decreases expression, decreases reaction, affects expression	3
trichostatin A	affects expression, increases expression	2
Arsenic Trioxide	increases expression, affects cotreatment	2
Tretinoin	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases secretion, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
ICG 001	increases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Wortmannin	decreases reaction, increases secretion	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	affects expression, increases reaction	1

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8PB	Abcam HCT 116 SIRPA KO	Cancer cell line	Male
CVCL_B9BG	Abcam MCF-7 SIRPA KO	Cancer cell line	Female
CVCL_B9RP	Abcam A-549 SIRPA KO	Cancer cell line	Male
CVCL_E6RT	Genomeditech CHO-K1 H_SIRPA	Spontaneously immortalized cell line	Female
CVCL_KA60	CHO-K1/SIRP alpha	Spontaneously immortalized cell line	Female
CVCL_TL22	HAP1 SIRPA (-) 1	Cancer cell line	Male
CVCL_XS81	HAP1 SIRPA (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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