Expression cloning of a human granulocyte colony-stimulating factor receptor: a structural mosaic of hematopoietin receptor, immunoglobulin, and fibronectin domains.

Abstract

We report the isolation from a placental library, of two cDNAs that can encode high affinity receptors for granulocyte colony-stimulating factor (G-CSF) when expressed in COS-7 cells. The cDNAs are predicted to encode integral membrane proteins of 759 and 812 amino acids in length. The predicted extracellular and membrane spanning sequences of the two clones are identical, as are the first 96 amino acids of their respective cytoplasmic regions. Different COOH termini of 34 or 87 residues are predicted for the two cDNAs, due apparently to alternate splicing. The receptor with the longer cytoplasmic domain is the closest human homologue of the murine G-CSF receptor recently described by Fukunaga et al. (Fukunaga, R., E. Ishizaka-Ikeda, Y. Seto, and S. Nagata. 1990. Cell. 61:341). A hybridization probe derived from the placental G-CSF receptor cDNA detects a approximately 3-kb transcript in RNAs isolated from placenta and a number of lymphoid and myeloid cells. The extracellular region of the G-CSF receptors is composed of four distinct types of structural domains, previously recognized in other cell surface proteins. In addition to the two domains of the HP receptor family-defining region (Patthy, L. 1990. Cell. 61:13) it incorporates one NH2-terminal Ig-like domain, and three additional repeats of fibronectin type III-like domains. The presence of both an NH2-terminal Ig-like domain and multiple membrane-proximal FN3-like domains suggests that the G-CSF receptor may be derived from an ancestral NCAM-like molecule and that the G-CSF receptor may function in some adhesion or recognition events at the cell surface in addition to the binding of G-CSF.

Interleukin‐6: Structure‐function relationships

“…The extracellular region of gp130 has the same modular structure as the G-CSF receptor Larsen et a!., 1990) including an N-terminal Ig-like domain and a CBD, which is followed by three FN I11 domains (Fig. 4).…”

“…Our model arose from a consideration of how one gp130 molecule might interact with two distinct sites on different E-6 molecules, as well as the nature of the site III interaction. We have taken into account that the extracellular region of gp130 has the same modular structure as the G-CSFR , Hibi et al, 1990Larsen et al, 1990), including an Ig-like domain that is lacking in the GHR (Leung et al, 1987). Both the Ig-like domain and the CBD of the G-CSFR are required for ternary complex formation with G-CSF (Hiraoka et al, 1995).…”

Increased expression of the differentiation-defective granulocyte colony-stimulating factor receptor mRNA isoform in acute myelogenous leukemia

“…14 The G-CSFR protein is a type I receptor, with singular extracellular, transmembrane, and cytoplasmic domains. 14,15 Receptor dimerization induced by ligand binding is required for downstream signaling events to occur. 14,[16][17][18][19][20][21][22][23][24][25][26][27] Functional studies of the G-CSFR have mapped proliferative signaling to the membrane proximal 96 amino acids of the cytoplasmic domain.…”

“…29,31 In humans, there are five mRNA isoforms encoding the G-CSFR, classes I-V, which differ in their transmembrane and/or cytoplasmic domains as a result of alternative pre-mRNA splicing patterns of the single gene transcript. 15,[32][33][34][35] The class I G-CSFR isoform, which is most homologous to the murine G-CSFR, contains the entire 183 amino acid cytoplasmic domain. The class II G-CSFR deletes the majority of the membrane spanning domain via alternative splicing and produces a soluble receptor; little is known about its function.…”

Characterization of the receptor binding determinants of granulocyte colony stimulating factor

“…The extracellular domains of the receptor consist of an amino-terminal immunoglobulin-like domain, followed by two cytokine receptor homology domains, and three membrane proximal fibronectin type 111 domains (Larsen et al, 1990).…”