SIRPA (Signal Regulatory Protein Alpha): Gene, Function, and Clinical Significance
A comprehensive biomedical overview of the SIRPA gene, its protein product, expression patterns, associated diseases, and mutations.
Gene Information Card
| Symbol | SIRPA |
|---|---|
| Full Name | Signal Regulatory Protein Alpha |
| Gene Type | Protein coding |
| Chromosomal Location | 20p13 |
| NCBI Gene ID | 140885 ncbi.nlm.nih.gov/gene/140885 |
| Ensembl ID | ENSG00000198053 |
| UniProt ID | P78324 |
| OMIM ID | 602461 |
| HGNC ID | HGNC:9662 |
| Aliases | CD172A, SHPS-1, SIRP, BIT, MFR, PTPNS1 |
Description
SIRPA encodes signal regulatory protein alpha, a transmembrane glycoprotein belonging to the immunoglobulin superfamily. It is expressed predominantly on myeloid cells (macrophages, dendritic cells, neutrophils) and also on neurons. SIRPA functions as an inhibitory receptor that binds to CD47, a 'don't eat me' signal, to regulate phagocytosis, immune homeostasis, and cell migration. Through its cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs), SIRPA recruits SHP-1/SHP-2 phosphatases to dampen signaling. It plays critical roles in immune tolerance, hematopoiesis, and neural development, and is implicated in cancer immune evasion and autoimmune diseases.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | SIRPA-CD47 interaction inhibits macrophage-mediated phagocytosis of tumor cells, promoting immune evasion. Overexpression of CD47 on tumors and SIRPA on myeloid cells leads to reduced anti-tumor immunity. | High CD47 expression correlates with poor prognosis in various cancers (e.g., AML, non-Hodgkin lymphoma). SIRPA polymorphisms affect CD47 binding affinity and cancer susceptibility (e.g., in lung cancer). |
| Alzheimer's disease | SIRPA is involved in microglial phagocytosis of amyloid-beta plaques. Altered SIRPA signaling may impair clearance of Aβ, contributing to neurodegeneration. | GWAS studies have linked SIRPA variants to Alzheimer's risk. Functional studies show SIRPA regulates microglial uptake of Aβ. |
| Atherosclerosis | SIRPA on macrophages interacts with CD47 on vascular cells to inhibit efferocytosis (clearance of apoptotic cells), leading to plaque necrosis. | Mouse models with SIRPA blockade show reduced atherosclerosis. Human plaques show increased CD47-SIRPA signaling. |
| Autoimmune diseases (e.g., systemic lupus erythematosus) | SIRPA modulates dendritic cell and macrophage activation, affecting immune tolerance. Dysregulation may promote autoimmunity. | SIRPA polymorphisms have been associated with SLE susceptibility in some populations. |
| Infectious diseases (e.g., HIV) | SIRPA-CD47 interaction influences viral entry and immune evasion. SIRPA on macrophages may affect HIV replication. | Studies show SIRPA expression on macrophages modulates HIV infection in vitro. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | High | High |
| Bone Marrow | High | High |
| Spleen | High | High |
| Lung | Medium | Medium |
| Liver | Low | Low |
| Brain | Medium | Medium |
| Kidney | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Monocytes | High | Key SIRPA-expressing cells |
| Macrophages | High | Regulates phagocytosis |
| Dendritic cells | High | Immune regulation |
| Neutrophils | Medium | Innate immunity |
| T cells | Low | Minimal expression |
| B cells | Low | Minimal expression |
| NK cells | Low | Minimal expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs1050792 (c.361A>G, p.Ile121Val) | Missense | Allele frequency ~0.3 (global) | Alters CD47 binding affinity; associated with cancer susceptibility and autoimmune risk. |
| rs6087670 (c.1003C>T, p.Arg335Trp) | Missense | Rare | May affect SIRPA signaling; reported in some cancer cohorts. |
| rs3739277 (c.1146A>G, p.Thr382Ala) | Missense | Allele frequency ~0.1 | Potential impact on protein stability; linked to Alzheimer's risk. |
| Somatic mutations in cancer | Various | Low frequency | May alter SIRPA function in tumor microenvironment; not well characterized. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in SIRPA are rare and not well documented. Complete knockout in mice leads to enhanced phagocytosis and reduced CD47-mediated inhibition, but no human germline loss-of-function has been reported. Somatic loss may contribute to increased immune surveillance.
Gain of Function (GOF)
Gain-of-function mutations that increase SIRPA-CD47 binding could enhance immune evasion. Some SNPs (e.g., rs1050792) may increase binding affinity, but functional evidence is limited.
Dominant Negative (DN)
No dominant-negative mutations have been described for SIRPA. The protein functions as a monomer, and mutations that disrupt ITIM signaling could act in a dominant-negative manner, but such variants are not yet identified.
View complete mutation data：
Gene Ontology (GO)
Pathways
• CD47/SIRPA signaling pathway
• Phagocytosis regulation
• Innate immune system
• Signal transduction (SHP-1/2 mediated)
• Cell adhesion and migration
Protein Summary
SIRPA is a type I transmembrane protein with an extracellular region containing three immunoglobulin-like domains (one V-set and two C1-set) and a cytoplasmic tail with ITIMs. It binds CD47 with high affinity, leading to phosphorylation of ITIMs and recruitment of SHP-1/SHP-2 phosphatases, which dephosphorylate downstream signaling molecules. This inhibits phagocytosis, modulates cytokine production, and regulates cell motility. SIRPA is critical for self-recognition and immune homeostasis. Its expression is tightly regulated, and dysregulation is implicated in cancer, neurodegeneration, and autoimmunity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SIRPA Knockout HEK293 Cell Line | EDJ-KQ17736 | Human | 140885 | Details Get a Quote |
| SIRPA Knockout A-549 Cell Line | EDJ-KQ19809 | Human | 140885 | Details Get a Quote |
| SIRPA Knockout HCT 116 Cell Line | EDJ-KQ19810 | Human | 140885 | Details Get a Quote |
| SIRPA Knockout HeLa Cell Line | EDJ-KQ19811 | Human | 140885 | Details Get a Quote |
