Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.
SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
also called the "don't eat me" signal. This interaction negatively controls effector function of
innate immune cells such as host cell
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
. SIRPα diffuses laterally on the
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
membrane and accumulates at a phagocytic synapse to bind CD47 and signal 'self', which inhibits the cytoskeleton-intensive process of phagocytosis by the macrophage.
This is analogous to the self signals provided by
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...
molecules to
NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
via Ig-like or
Ly49 Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells (some CD8+ and CD3+ T lymphocytes, intestinal epithelial lymphocytes (IELs), NKT cells, uterine NK cells (uNK) cells, macrophages ...
receptors.
NB. Protein shown to the right is CD47 not SIRP α.
Structure
The cytoplasmic region of SIRPα is highly conserved between rats, mice and humans. Cytoplasmic region contains a number of
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residues, which likely act as
ITIMs. Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and
SHP2
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
. The extracellular region contains three
Immunoglobulin superfamily
The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily ba ...
domains – single V-set and two C1-set
IgSF domains. SIRP β and γ have the similar extracellular structure but different cytoplasmic regions giving contrasting types of signals. SIRP α polymorphisms are found in ligand-binding
IgSF V-set domain but it does not affect ligand binding. One idea is that the polymorphism is important to protect the receptor of pathogens binding.
Ligands
SIRPα recognizes
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
, an anti-phagocytic signal that distinguishes live cells from dying cells. CD47 has a single Ig-like extracellular domain and five membrane spanning regions. The interaction between SIRPα and CD47 can be modified by
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
or cleavage of the receptor, or interaction with
surfactant proteins.
Surfactant protein A
Surfactant protein A is an innate immune system collectin. It is water-soluble and has collagen-like domains similar to SP-D. It is part of the innate immune system and is used to opsonize bacterial cells in the alveoli marking them for phagocyt ...
and
D are soluble ligands, highly expressed in the lungs, that bind to the same region of SIRPα as
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
and can therefore competitively block binding.
Signalling
The extracellular domain of SIRP α binds to
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
and transmits intracellular signals through its cytoplasmic domain. CD47-binding is mediated through the NH2-terminal V-like domain of SIRP α. The cytoplasmic region contains four
ITIMs that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinase
SHP2
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in huma ...
. SIRP α has been shown to bind also phosphatase
SHP1
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the ''PTPN6'' gene.
Function
The protein encoded by this gene is a member ...
, adaptor protein
SCAP2 and
FYN
Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition of
myosin
Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.
The first myosin ...
accumulation at the cell surface and results in the inhibition of
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
.
Cancer
Cancer cells highly expressed
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
that activate SIRP α and inhibit
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
-mediated destruction. In one study, they engineered high-affinity variants of SIRP α that antagonized
CD47
CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and als ...
on cancer cells and caused increase
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
of cancer cells.
Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.
Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
/ref>
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
{{Clusters of differentiation
Clusters of differentiation