CD47 - CD47 molecule |Elisa - Clia - Antibody - Protein

Background

CD47, also known as integrin-associated protein (IAP), is a widely expressed transmembrane glycoprotein that plays a critical role in immune regulation, cell signaling, and cellular adhesion. It is a member of the immunoglobulin superfamily and is involved in numerous biological processes, including immune evasion, apoptosis, angiogenesis, and cell migration. One of CD47's primary functions is to act as a "don't eat me" signal to prevent macrophage-mediated phagocytosis, which is a key component in the immune system's ability to clear dead cells and pathogens.

CD47 interacts with signal regulatory protein alpha (SIRPα), a receptor primarily expressed on myeloid cells, such as macrophages and dendritic cells. The binding of CD47 to SIRPα sends an inhibitory signal to macrophages, preventing the phagocytosis of CD47-expressing cells. This interaction plays a critical role in protecting normal cells from immune clearance but can also be exploited by cancer cells to evade immune detection and destruction.

Additionally, CD47 is involved in regulating a variety of cellular processes, including vascular homeostasis, immune cell trafficking, and thrombus formation. Its expression is upregulated in many types of cancer, where it contributes to tumor immune evasion by blocking the phagocytic activity of macrophages, making it a key target in cancer immunotherapy.

Protein Structure

CD47 is a type I transmembrane protein, composed of several distinct structural regions that enable its diverse biological functions:

Extracellular Domain:

• The extracellular portion of CD47 contains a single immunoglobulin-like (Ig) variable domain, which belongs to the immunoglobulin superfamily (IgSF). This domain is critical for its interaction with SIRPα, the receptor on macrophages that mediates the inhibitory "don't eat me" signal.
• The extracellular domain is also involved in interactions with other ligands, such as thrombospondin-1 (TSP-1), a multifunctional protein that plays roles in angiogenesis, apoptosis, and immune regulation.
• The Ig-like domain is stabilized by disulfide bonds, contributing to the protein’s structural integrity and functional capacity in cell signaling.

Transmembrane Domain:

• CD47 spans the membrane with five membrane-spanning α-helices. This is unusual for proteins in the immunoglobulin superfamily, which typically have a single transmembrane domain. These transmembrane helices are involved in interactions with integrins, particularly β3 integrins (e.g., integrin αvβ3), which link CD47 to the cytoskeleton and intracellular signaling pathways.
• This domain anchors CD47 to the plasma membrane and contributes to its localization in specific membrane microdomains, such as lipid rafts, where it can interact with other signaling molecules.

Cytoplasmic Tail:

• The cytoplasmic tail of CD47 is short and does not have enzymatic activity itself. However, it interacts with intracellular proteins that are involved in signal transduction, such as Gi proteins. These interactions regulate a variety of downstream signaling pathways that modulate cell migration, adhesion, and immune responses.
• The tail is involved in coupling CD47 to intracellular signaling cascades, influencing processes such as cell survival, proliferation, and apoptosis.

Classification and Subtypes

CD47 is encoded by the CD47 gene and is considered a single molecule without well-established subtypes. However, the diversity in its function comes from its ability to interact with different ligands and receptors, such as SIRPα and thrombospondin-1, and its association with integrins.

There are alternative splice variants of CD47 that have been identified, but their specific functions and regulatory roles are not fully understood. These isoforms may vary in their cytoplasmic tail or other regions, potentially affecting their intracellular signaling properties.

Function and Biological Significance

CD47 plays a variety of roles in both immune regulation and cellular homeostasis:

Immune Evasion:

• CD47 serves as a key regulator of innate immune responses by interacting with SIRPα on macrophages. The engagement of CD47 with SIRPα triggers an inhibitory signal that blocks macrophage phagocytosis. This "don't eat me" signal is crucial for preventing the clearance of healthy cells, especially red blood cells, platelets, and other self-cells.
• This mechanism is exploited by tumor cells, which overexpress CD47 to avoid being recognized and phagocytosed by immune cells, particularly macrophages. This allows cancer cells to evade immune surveillance and contributes to tumor progression.

Role in Cancer:

• The overexpression of CD47 is observed in a variety of malignancies, including leukemia, lymphoma, and solid tumors such as breast and ovarian cancers. The CD47-SIRPα interaction is a therapeutic target in cancer, with several anti-CD47 antibodies under development aiming to block this interaction, allowing immune cells to recognize and destroy tumor cells.
• Anti-CD47 therapies are being explored as a potential way to restore the immune system’s ability to clear cancer cells, making CD47 a promising target for cancer immunotherapy.

Cell Adhesion and Migration:

• CD47 interacts with integrins, particularly αvβ3, playing a role in cell adhesion, migration, and cytoskeletal organization. These processes are important during angiogenesis, wound healing, and immune cell trafficking.
• The interaction between CD47 and thrombospondin-1 can regulate cell migration and adhesion, influencing processes like endothelial cell function, vascular remodeling, and tumor metastasis.

Vascular Homeostasis and Angiogenesis:

• CD47, through its interaction with thrombospondin-1, can inhibit angiogenesis (the formation of new blood vessels) by modulating endothelial cell function. This anti-angiogenic role is important in maintaining vascular homeostasis and has implications for cancer, where blocking angiogenesis can be a strategy to starve tumors of nutrients and oxygen.
• Inhibition of angiogenesis through the CD47-thrombospondin-1 axis is a potential target for anti-cancer therapies aiming to reduce tumor blood supply.

Role in Apoptosis:

• CD47 is involved in the induction of apoptosis in some contexts, especially in association with thrombospondin-1. Thrombospondin-1 binding to CD47 can lead to apoptosis in endothelial cells and T cells, which plays a role in immune regulation and tissue remodeling.
• This pathway can also be targeted in cancer therapy to promote apoptosis in tumor cells.

T-cell Activation:

• CD47 has been shown to modulate T-cell activation and function. Its interaction with SIRPα on dendritic cells can influence T-cell priming, contributing to the adaptive immune response. CD47 can also regulate T-cell apoptosis, helping to maintain immune homeostasis.

Clinical Issues

Cancer:

• CD47 is a key player in tumor immune evasion. Many cancers upregulate CD47 to protect themselves from being phagocytosed by macrophages. Blocking the CD47-SIRPα interaction is a promising therapeutic strategy in oncology, with several CD47-targeting antibodies in clinical trials.
• Early-phase clinical trials with anti-CD47 monoclonal antibodies, such as magrolimab, have shown promise in treating cancers like acute myeloid leukemia (AML) and non-Hodgkin lymphoma by enhancing macrophage-mediated clearance of tumor cells.

Autoimmune Disorders:

• Dysregulation of the CD47-SIRPα axis has been implicated in some autoimmune diseases, where improper recognition of self-cells by macrophages may lead to tissue damage. Therapies that modulate CD47 activity could potentially be beneficial in treating conditions where immune tolerance is disrupted.

Transplantation:

• CD47 plays a role in the survival of transplanted organs and tissues. Overexpression of CD47 on grafts can reduce graft rejection by preventing the immune system from attacking the transplanted tissue. This makes CD47 a potential target for therapies aimed at enhancing transplant survival.

Cardiovascular Disease:

• CD47’s role in angiogenesis and vascular remodeling suggests its involvement in cardiovascular diseases, including atherosclerosis and ischemic injury. Therapeutic strategies that inhibit the CD47-thrombospondin-1 interaction could potentially promote angiogenesis and improve outcomes in cardiovascular diseases.

Summary

CD47 is a transmembrane glycoprotein that plays a pivotal role in immune regulation, particularly in preventing the phagocytosis of self-cells by macrophages through its interaction with SIRPα. Structurally, CD47 is characterized by its Ig-like extracellular domain, five transmembrane α-helices, and a short cytoplasmic tail, which mediate interactions with integrins and signaling molecules.

Its primary function is to act as a "don't eat me" signal, a mechanism exploited by cancer cells to evade immune clearance. This makes CD47 a crucial target for cancer immunotherapy, with several therapeutic antibodies under investigation. Beyond cancer, CD47 is involved in processes such as angiogenesis, apoptosis, immune cell trafficking, and transplantation biology, highlighting its broad biological significance. Understanding CD47's structure and function is key to developing targeted therapies for various immune, vascular, and neoplastic disorders.