Granulocyte-macrophage colony-stimulating factor receptor

Gene for α chain is in pseudoautosomal region (PAR) of X and Y chromosomes at the very tip of the chromosomes, near telomere regions and also genes encoding IL-3α with which they share some similarities.[9] Along the gene are several transcription regulatory binding sites with common binding motifs for such transcription factors as GATA, C/EBP or NF-κB.[6]

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.[6] Extracellular domain contains cytokine receptor domain for binding its cognate ligand with conserved cysteine residues, WSXWS motif and 11 potential N-glycosylation sites for oligosaccharides, which are important for ligand binding and signalling. Cytoplasmic domain is made of short proline-rich motif and has no intrinsic enzymatic activity.[6][9][10] Similar to such motif is also Box1 sequence in 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.[9] 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).[6][11] 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, erythropoietin receptor). 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.[6] Cytoplasmic domain serves as a signal transducer.[9][10]

α chain can be modified in post-transcriptional manner by alternative splicing creating different variant of mRNA. 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 and chorio-carcinoma cells. Splicing products on the 5´end were found in primary haematopoietic cells and acute myeloid leukemia blasts.[6][12]

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.[6][12]

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 phosphatase with SH2 binding domain or by members of SOCS family which also possess SH2 domain. After direct ligation with JAK kinase, they mediate degradation in proteasome.[11] 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.[6][8]