The granulocyte-macrophage colony-stimulating factor receptor also known as CD116 (Cluster of Differentiation 116), is a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for
granulocyte-macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...
, which stimulates the production of white blood cells.
In contrast to
M-CSF
The colony stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF), is a secreted cytokine which causes hematopoietic stem cells to differentiate into macrophages or other related cell types. Eukaryotic cells also ...
and
G-CSF
Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.
Functiona ...
which are lineage specific, GM-CSF and its receptor play a role in earlier stages of development. The receptor is primarily located on
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s,
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s and
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s/
macrophages, it is also on
CD34+ progenitor cells (
myeloblasts) and precursors for
erythroid
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
and
megakaryocytic lineages, but only in the beginning of their development.
It is associated with
Surfactant metabolism dysfunction type 4.
Structure
The granulocyte-macrophage colony-stimulating factor receptor is a
heterodimer composed of at least two different subunits; an α chain, and a β chain which is also present in the receptors for
IL-3 and
IL-5. The α subunit contains a binding site for granulocyte macrophage colony-stimulating factor, but associates with the ligand only with low affinity.
The β chain is involved in signal transduction and formation of high affinity receptor complex together with α chain. Furthermore association of the α and β subunits results in receptor activation.
α chain
Gene for α chain is in
pseudoautosomal region
The pseudoautosomal regions, PAR1, PAR2, are homologous sequences of nucleotides on the X and Y chromosomes.
The pseudoautosomal regions get their name because any genes within them (so far at least 29 have been found for humans) are inherited ...
(PAR) of
X and
Y chromosome
The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abse ...
s at the very tip of the chromosomes, near
telomere
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
regions and also genes encoding IL-3α with which they share some similarities.
Along the gene are several transcription regulatory binding sites with common binding motifs for such transcription factors as GATA,
C/EBP
CCAAT-enhancer-binding proteins (or C/EBPs) is a family of transcription factors composed of six members, named from C/EBPα to C/EBPζ. They promote the expression of certain genes through interaction with their promoters. Once bound to DNA, C ...
or
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
.
α chain is 80kDa type I transmembrane protein composed of 3 domains: extracellular, transmembrane and cytoplasmic. Mature polypeptide contains 378 amino acids - 298 amino acids in extracellular domain, 26 in transmembrane domain, 54 in short cytoplasmic tail, plus 22 amino acid long signal peptide, which is cleaved off during translation.
Extracellular domain contains cytokine receptor domain for binding its cognate ligand with conserved cysteine residues, WSXWS motif and 11 potential
N-glycosylation
''N''-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom (the amide nitrogen of an asparagine (Asn) residue of a protein), ...
sites for
oligosaccharide
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...
s, which are important for ligand binding and signalling. Cytoplasmic domain is made of short proline-rich motif and has no intrinsic enzymatic activity.
Similar to such motif is also Box1 sequence in β chain.
β chain
β chain is crucial for enhancement of binding affinity to the ligand and transduces signal of the activated receptor complex. It is shared with other cytokine receptors IL-3 and IL-5.
Its location is on chromosome 22. Surrounding sequences provide binding sites for several regulatory transcription factors similar to those for α chain (GATA, C/EBP, NF-κB).
β subunit forms mature 95kDa 800 amino acid long polypeptide with 3 domains: extracellular, transmembrane and cytoplasmic. Extracellular domain contains haematopoietin domains, also known as cytokine receptor modules, which can be found in other cytokine receptors (
growth hormone receptor
Growth hormone receptor is a protein that in humans is encoded by the ''GHR'' gene. GHR orthologs have been identified in most mammals.
Structure
Growth hormone receptor (GHR) is a transmembrane protein consisting of 620 amino acids. The recep ...
,
erythropoietin receptor
The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the ''EPOR'' gene. EpoR is a 52kDa peptide with a single carbohydrate chain resulting in an approximately 56-57 kDa protein found on the surface of EPO responding cells. ...
). In the membrane distant part are typically cysteine residues forming disulphide bonds, proline pair, which devies the extracellular domain into two
fibronectin type III-like subdomains in seven stranded
β-barrel structure. In the membrane proximal region is then a WSXWS motif as is in α chain.
Cytoplasmic domain serves as a signal transducer.
Structural variants
α chain can be modified in post-transcriptional manner by
alternative splicing creating different variant of
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
. Splicing on 3´end produces transcript where 25 amino acids in C-terminal region are completely replaced by 35 new amino acids. Such protein is functional, but 10 times less abundant. Another splicing variant lacks both transmembrane and cytoplasmic domains. Remaining extracellular domain acts as a soluble GM-CSFRα and have been identified in
bone marrow, monocytes and macrophages,
placenta
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
and
chorio-carcinoma cells. Splicing products on the 5´end were found in primary haematopoietic cells and
acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...
blasts.
β subunit can be found in two distinct isoforms: classical full-length protein and alternative form with deletions in transmembrane domain. Deletions results in truncated peptide with 23 original amino acids in the membrane proximal cytoplasmic region and 23 new ones in C-terminal tail. This shorter isoform is unable to transduce any signals, thus acts as a negative inhibitor. Significantly upregulated production is in blasts from acute myeloid leukemia patients.
Signal transduction
Upon dimerisation of the α and β subunits the β subunit becomes phosphorylated on tyrosine residues in its cytoplasmic domain, where are many regions participating in different cell signalling mechanisms for proliferation, differentiation and survival. Formation of high affinity receptor complex includes specific interactions between both subunits and ligand. Interactions then mediate conformational changes and subsequent receptor activation. Receptor is either functional in single heterodimer α1β1 or in dimerised complexes α2β2 joined by intermolecular disulphide bonds.
For full activation oligomerization of the receptor is crucial, it is formed into hexamer composed of two GM-CSF, two α and two β subunits or dodecamer which is composed of two hexamers.
Phosphorylation is mediated by
tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
s, members of the
Janus kinase
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoveries ...
(JAK) family, which are constitutively associated with cytoplasmic domain.
Activated kinases then phosphorylate tyrosine residues on cytoplasmic domain of β subunit, thus creating docking sites for
Src homology 2 (SH2) domain-containing signalling proteins like
Shc and
STATs.
These interactions trigger downstream signalling pathways, depending on the location of phosphorylated tyrosine residues in the chain. Membrane proximal section is known to be responsible for proliferation by activating
STAT5 and c-myc.
Membrane distal section is then required for differentiation and survival by prevention of
apoptosis and activation of
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
and
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
pathways.
[ ]
Downregulation of signal transduction
Simultaneously with receptor activation goes hand in hand its downregulation, that prevents unwanted overactivation. Controlling mechanisms are mainly aimed at inhibition of JAK kinase activity by
SHP-1
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 ...
tyrosine phosphatase with SH2 binding domain or by members of
SOCS
SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway.
Genes
* CISH
* SOCS1
* SOCS2
* SOCS3
* SOCS4
* SOCS5
* SOCS6
* SOCS7
Suppressor of cytokine signaling 7 is a pro ...
family which also possess SH2 domain. After direct ligation with JAK kinase, they mediate degradation in
proteasome.
Other possibility of downregulation is degradation of phosphorylated β subunit and subsequent internalization of the receptor/ligand complex. Rate of such process positively correlates with amount of ligand/receptor complexes. In addition, after stimulation of β subunit mRNA levels coding α chain decrease and on the contrary expression of soluble α subunit is upregulated. Soluble GM-CSFRα then clutches free ligands with similar affinity as membrane receptor and prevents binding of GM-CSF to the cell surface. GM-CSFRα can be also cleaved off of the membrane receptor.
Role in development
Different expression of GM-CSFR subunits on hematopoietic cells mediates maturation of various lineages. For example in quiescent hematopoietic stem cells the β chain is expressed at very low levels and the amount increases along initial differentiation of erythroid, megakaryocytic, granulocytic and monocytic lineages. In the first two mentioned lineages the expression eventually vanishes completely, in granulocytes and monocytes persists and continues to grow during their differentiation. In monocytes and mainly neutrophils receptor regulates proliferation, maturation and overall survival.
Kinetics of the receptor in immature and mature myeloid cells in response to GM-CSF is readily regulated by internalization or just by above mentioned degradation and desensitization of β subunit (mainly in the earlier hematopoietic development).
Role in malaria pathogenesis
It was shown that defective dendritic cell (DC) differentiation in malaria at least partially caused by GM-CSFR dysregulation and GM-CSFR modification by lipoperoxidation product 4-HNE via direct interaction with its CD116 subunit.
References
Further reading
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External links
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{{Cytokine receptor modulators
Clusters of differentiation
Type I cytokine receptors