SIRPA

What is SIRPA Protein?

SIRPA gene (signal regulatory protein alpha) is a protein coding gene which situated on the short arm of chromosome 20 at locus 20p13. 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. The SIRPA protein is consisted of 504 amino acids and SIRPA molecular weight is approximately 55.0 kDa.

What is the Function of SIRPA Protein?

SIRPA is a member of the immunoglobulin superfamily and is mainly expressed in neurons, dendritic cells and macrophages. It is a transmembrane protein capable of binding to its cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2. SIRPA interacts with the widely expressed transmembrane protein CD47 to form an intercellular communication system. The binding of SIRPA and CD47 is very important for regulating cell migration and phagocytosis. In addition, SIRPA proteins are involved in a variety of biological processes, including inhibition of cell signaling coupled to receptor tyrosine kinases, regulation of phagocytosis, negative regulation of mast cell activation and dendritic cell activation, and role in antiviral immunity.

SIRPA Related Signaling Pathway

When SIRPA binds to CD47, it can trigger a series of downstream signaling processes, including activation of SHP-1 and SHP-2, which affect cell phagocytosis, cytokine production, and cell proliferation and differentiation. Especially in the immune system, SIRPA-CD47 signaling pathway plays an important role in maintaining the lifespan of red blood cells, regulating the implantation of hematopoietic stem cells, and tumor immune surveillance. Tumor cells bind to SIRPA through high expression of CD47, which may evade clearance by macrophages, thus promoting tumor growth and metastasis.

Fig1. Schematic model of combination therapy targeting both the CD47-SIRPα and PD-1-PD-L1 axes. (Naomichi Koga, 2021)

SIRPA Related Diseases

SIRPA is associated with a variety of pathological processes, and its abnormal function or change of expression level is related to the occurrence and development of some diseases. For example, SIRPA gene variation is associated with thrombocytopenia, affecting platelet clearance and homeostasis. The role of SIRPA-CD47 signaling pathway in tumor immune surveillance implies its potential target value in cancer therapy, especially in influencing the clearance of tumor cells by regulating the phagocytosis activity of macrophages. The role of SIRPA in autoimmune diseases suggests that it may influence dendritic cell function and induction of autoimmune responses, which is particularly important in diseases such as experimental autoimmune encephalomyelitis, contact dermatitis, and colitis. In addition, SIRPA is also involved in the regulation of bone homeostasis, and its abnormality may be associated with bone disease.

Bioapplications of SIRPA

The applications of SIRPA are mainly in the fields of medicine and biotherapy, especially as a potential target for immune regulation and cancer therapy. The interaction of SIRPA with its ligand CD47 plays a key role in regulating the phagocytosis of macrophages, a mechanism that offers the possibility of developing new cancer treatment strategies, such as promoting the clearance of tumor cells by blocking the SIRPA-CD47 signaling pathway. In addition, SIRPA's role in maintaining red blood cell lifespan, regulating hematopoietic stem cell implantation, and influencing dendritic cell function makes it potentially useful in the treatment of blood diseases and autoimmune diseases. In drug development, antibodies or small molecule drugs that target SIRPA may help treat or manage these diseases. At the same time, SIRPA's role in bone homeostasis also suggests its potential application in the treatment of bone diseases. Therefore, the modulators of SIRPA may become novel therapeutic tools for the treatment of many diseases.

Case Study 1: James D Londino, 2015

Signal regulatory protein α (SIRPα) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRPα ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-κB signaling in macrophages. Here researchers observed that proteolysis of SIRPα during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. They mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRPα fragment by γ-secretase was identified. Ectopic expression of a SIRPα mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-κB pathway and suppressed STAT1 phosphorylation in response to TNFα to a greater extent than expression of wild-type SIRPα. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRPα fragments in cells resulted in enhanced STAT-1 and NF-κB pathway activation.

Fig1. HeLa cells were transfected with a WT SIRPα-expressing plasmid.

Fig2. SIRPα mutant plasmids were expressed in HeLa cells and WB was performed on different components.

Case Study 2: Xiaojing Ye, 2016

Signal regulatory protein α (SIRPα) is a cell-surface protein expressed on macrophages that are regarded as an important component of the tumor microenvironment. The expression of SIRPα in oral leukoplakia (OLK) and oral squamous cell carcinoma (OSCC), and further explored the role of SIRPα on the phenotype, phagocytosis ability, migration, and invasion of macrophages in OSCC were investigated. The expression of SIRPα in OLK was higher than in OSCC, correlating with the expression of CD68 and CD163 on macrophages. After cultured with the conditioned media of oral cancer cells, the expression of SIRPα on THP-1 cells was decreased gradually. In co-culture system, macrophages were induced into M2 phenotype by oral cancer cells. Blockade of SIRPα inhibited phagocytosis ability and IL-6, TNF-α productions of macrophages. In addition, the proliferation, migration, and IL-10, TGF-β productions of macrophages were upregulated after blockade of SIRPα. Macrophages upregulated the expression of SIRPα and phagocytosis ability, and inhibited the migration and invasion when the activation of NF-κB was inhibited by pyrrolidine dithiocarbamate ammonium (PDTC).

Fig3. The expression of SIRPα was decreased gradually when macrophages were co-cultured with supernatant of SCC-9.

Fig4. The expression of SIRPα in Cal-27 group was increased than PMA group.

SIRPA has several biochemical functions, for example, SH3 domain binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SIRPA itself. We selected most functions SIRPA had, and list some proteins which have the same functions with SIRPA. You can find most of the proteins on our site.

SIRPA has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SIRPA here. Most of them are supplied by our site. Hope this information will be useful for your research of SIRPA.

NOL3;PTPN6;TRIM2;HTT;GRB2