SIRPA - signal regulatory protein alpha |Elisa - Clia - Antibody - Protein

Background

Signal regulatory protein alpha (SIRPA) is a transmembrane glycoprotein encoded by the SIRPA gene in humans, primarily expressed on myeloid cells such as macrophages, dendritic cells, and neutrophils, and to a lesser extent on neurons. SIRPA belongs to the immunoglobulin superfamily (IgSF) and functions as an inhibitory receptor, playing a critical role in immune homeostasis, cellular signaling, and cell-cell interactions. SIRPA interacts primarily with CD47, a widely expressed protein known as the “don’t eat me” signal on host cells. This interaction is fundamental for immune surveillance, as it prevents macrophages and other immune cells from targeting healthy self-cells for phagocytosis, thereby maintaining tolerance to self while supporting immune responses against foreign antigens and damaged cells.

SIRPA is integral in modulating immune responses and is implicated in a range of physiological processes, including cell migration, cell adhesion, and tissue homeostasis. Research indicates that SIRPA is not only crucial in the innate immune system but also impacts adaptive immunity. Dysregulation or mutations of SIRPA have been linked to autoimmunity, cancer, and other pathologies due to its role in immune evasion, particularly in the context of cancer, where many tumor cells upregulate CD47 to escape immune clearance.

Protein Structure

SIRPA has a unique structure that supports its role in signal transduction and immune regulation. Its main structural features include:

Extracellular Domain:

• SIRPA’s extracellular portion is composed of three immunoglobulin (Ig)-like domains: one N-terminal variable (V)-type Ig-like domain followed by two constant (C1)-type Ig-like domains.
• The N-terminal domain, specifically, is responsible for binding to CD47, allowing SIRPA to recognize “self” cells. This Ig-like domain is essential for SIRPA-CD47 interactions, which prevent phagocytosis by sending an inhibitory signal to immune cells.
• This binding induces conformational changes necessary for downstream intracellular signaling cascades, particularly through its impact on the protein's inhibitory function.

Transmembrane Domain:

• SIRPA contains a single hydrophobic transmembrane region that anchors it to the plasma membrane. This domain enables SIRPA to position its extracellular Ig-like domains for optimal interaction with CD47.
• The transmembrane region also helps localize SIRPA in lipid rafts, which are membrane microdomains essential for signal transduction in immune cells. This placement within lipid rafts enhances SIRPA’s interactions with signaling proteins and regulators.

Cytoplasmic Tail with Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs):

• SIRPA’s cytoplasmic region contains four ITIM motifs, which are sequences that recruit and activate inhibitory phosphatases, particularly SHP-1 (Src homology region 2 domain-containing phosphatase-1) and SHP-2. These ITIM motifs are crucial for transmitting inhibitory signals inside the cell.
• Upon binding to CD47, ITIMs in the SIRPA cytoplasmic tail become phosphorylated, recruiting SHP-1 and SHP-2 to dephosphorylate signaling intermediates, thereby reducing cell activation and preventing phagocytosis or further immune responses.
• The ITIM motifs are necessary for suppressing cell responses by blocking signaling pathways related to actin cytoskeleton rearrangement, cell motility, and cytokine production.

Classification and Subtypes

SIRPA is a member of the signal regulatory protein (SIRP) family, which includes several isoforms. The SIRP family itself is part of the larger IgSF. The SIRP family includes three main members: SIRPA, SIRPB, and SIRPG. Each of these family members differs slightly in structure, binding partners, and biological functions:

SIRPA:

• Expressed primarily on myeloid cells and neurons, SIRPA interacts with CD47, modulating immune responses and preventing “self” cell phagocytosis.

SIRPB:

• SIRPB, unlike SIRPA, typically lacks a significant cytoplasmic tail and does not contain ITIMs. It serves as an activating receptor and associates with the DAP12 adapter protein to mediate immune cell activation.

SIRPG:

• SIRPG is expressed mainly in lymphoid tissues and interacts with CD47, though with lower affinity compared to SIRPA. SIRPG’s functions are less understood but may involve T-cell activation and modulation.

Function and Biological Significance

SIRPA’s primary function is to act as an inhibitory receptor that maintains immune tolerance and modulates immune cell activation. Major roles include:

Immune Regulation:

• The SIRPA-CD47 interaction is critical for preventing autoimmunity, as it signals to macrophages and other immune cells to avoid phagocytosing healthy cells. By engaging with CD47, SIRPA transmits an inhibitory signal that recruits SHP-1 and SHP-2, ultimately blocking pathways that would otherwise lead to cytoskeletal rearrangements and engulfment of “self” cells.
• This interaction plays a key role in balancing immune surveillance with self-tolerance, allowing immune cells to identify and clear aged or damaged cells while sparing healthy cells.

Role in Cancer:

• Many cancer cells upregulate CD47 as a mechanism to evade immune detection by binding to SIRPA on macrophages, sending a “don’t eat me” signal. This interaction allows tumors to resist phagocytosis and immune clearance, facilitating tumor survival and growth.
• Blocking the SIRPA-CD47 interaction has become a promising strategy in cancer immunotherapy, aiming to enhance macrophage-mediated phagocytosis of tumor cells.

Neuronal Functions:

• SIRPA is also expressed in neurons, where it modulates cell adhesion and migration, impacting neural development and maintenance. Through interaction with other cellular adhesion molecules, SIRPA can influence neuron morphology and synaptic functions, although these functions are not as well characterized as its role in immune regulation.

Inflammatory Responses:

• In inflammatory conditions, SIRPA expression on immune cells can limit excessive inflammation by modulating cytokine release and immune cell activation. This function is especially relevant in chronic inflammation, where SIRPA may help curb tissue damage.

Clinical Issues

Dysregulation of SIRPA signaling is associated with several clinical conditions:

Cancer:

• Many cancers, including hematological malignancies and solid tumors, exploit the SIRPA-CD47 pathway to evade immune responses. High CD47 expression on tumors correlates with poorer prognosis in several cancer types.
• Immunotherapies targeting CD47 or SIRPA are under investigation to disrupt this inhibitory signal, enhancing immune system recognition and clearance of tumor cells.

Autoimmune Diseases:

• Given its role in maintaining immune tolerance, SIRPA dysfunction can contribute to autoimmunity. In conditions where SIRPA signaling is deficient or improperly regulated, there may be increased phagocytosis of self-cells, leading to chronic inflammation and tissue damage.

Neurodegenerative Diseases:

• Abnormal SIRPA expression or signaling has been observed in neurodegenerative disorders, where it may contribute to synaptic and neuronal dysfunction. Although studies are still ongoing, SIRPA may play a role in the pathogenesis of diseases like Alzheimer’s through its interactions in neuronal tissue.

Chronic Inflammatory Disorders:

• SIRPA’s role in modulating inflammation has implications in chronic inflammatory diseases, where excessive immune activation and cell turnover occur. Its involvement in limiting inflammatory cytokine production suggests potential therapeutic applications for targeting SIRPA pathways to manage inflammation.

Summary

SIRPA is a pivotal immune regulatory protein that prevents phagocytosis of self-cells through its interaction with CD47, playing a central role in maintaining immune tolerance and cellular homeostasis. Structurally, SIRPA consists of an extracellular region with Ig-like domains for CD47 binding, a transmembrane domain, and a cytoplasmic tail containing ITIM motifs. These structural features allow SIRPA to function as an inhibitory receptor on myeloid cells, preventing unwanted immune activation. Beyond immunity, SIRPA has implications in cancer, neurobiology, and inflammation, with dysregulated signaling linked to tumor immune evasion, autoimmune diseases, and chronic inflammatory disorders. The therapeutic potential of targeting SIRPA-CD47 interactions is particularly prominent in cancer, where blocking this axis can enhance immune clearance of tumor cells.