GM-CSF receptors

The intact GM-CSF receptor is a heterodimer, consisting of a low-affinity a-chain and a P-chain, which also forms part of the IL-3 and IL-5 receptors. (The P-chain alone does not bind GM-CSF.) The a-chain is an 80 kDa glycoprotein and exhibits only a short intracellular domain. The larger P-chain (130 kDa) displays a significant intracellular domain. Signal transduction involves the (tyrosine) phosphorylation of a number of cytoplasmic proteins (Figure 10.2). 

Figure 10.2 The GM-CSF receptor. Ligand binding appears to promote the phosphorylation of various cytoplasmic polypeptide substrates (at least in part via an associated JAK2), leading to signal transduction...

The properties of GM-CSF and the GM-CSF receptor are given in section 2.2.4. GM-CSF acts on mature neutrophils over the concentration range 1-100 pM. It does not stimulate the generation of oxidant secretion in cells in suspension, but rather primes their ability to generate oxidants when the neutrophils are exposed to a second stimulus primed neutrophils generate greater levels of oxidants compared to unprimed neutrophils (see 7.2 for... 

Kinoshita, T., Yokota, T., Arai, K., and Miyajima, A., 1995, Suppression ofapoptotic death in hematopoietic cells by signaling through the 1L-3/GM-CSF receptors. EMBOJ. 14 266-275. 

Geijsen N, Koenderman L, Coffer PJ. 2001. Specificity in cytokine signal transduction Lessons learned from the IL-3/IL-5/GM-CSF receptor family. Cytokine Growth Factor Rev. 12 19-25. 

Sato N, Sakamaki K, Terada N, Arai K, Miyajima A. 1993. Signal transduction by the high-affinity GM-CSF receptor Two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J. 12 4181—4189. 

W8. Watanabe, S., Itoh, T., and Arai, K., Roles of JAK kinases in human GM-CSF receptor signal transduction. J. Allergy Clin. Immunol. 98, S183—S191 (1996). 

R10. Roklin, O. W., Griebling, T. L., Karassina, N. V., Raines, M. A., and Cohen, M. B., Human prostate carcinoma cell lines secrete GM-CSF and express GM-CSF-receptor on their cell surface. Anticancer Res. 16, 557—563 (1996). 

Woodcock, J. M., McClure, B. J., Stomski, F. C., Elliott, M.J., Bagley, C.J., and Lopez, A. F. (1997). The human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor exists as a preformed receptor complex that can be activated by GM-CSF, interleukin-3, or interleukin-5. Blood 90, 3005—3017. 

Separate and specific receptors for each CSF are coexpressed on granulocytes and monocytes and they show no cross competition for their respective ligands However, a hierarchical down modulation has been observed, e.g. occupancy of multi-CSF receptor decreases the binding by all other receptors of their specific ligands occupancy of GM-CSF receptors cau-... 

Human GM-CSF receptor is composed of at least 2 subunits the 3-subunit is identical with a subunit of the receptors for interleukin-3 and interleukin-5. Both subunits have domains that are structurally related to a fibronectin type III domain, a structure that is conserved in all members of the cytokine receptor superfamily. Genomic DNA clones containing the entire coding sequence of the a-subunit have been isolated and characterized [Y.Nakagawa etal. J. Biol. Chem. 269 (1994) 10905-10912). 

Nishijima I, Nakahata T, Hirabayashi Y et al. (1997). A human GM-CSF receptor expressed in transgenic mice stimulates proliferation and differentiation of hemopoietic progenitors to all lineages in response to human GM-CSF. Molecular and Cellular Biology, 6 497-508... 

The functional significance of these cytokine changes in acute vs. chronic AD skin lesions is supported by in vivo studies of cytokine receptor mRNA expression (27). These studies have demonstrated that acute AD is associated with a high expression of IL-4 receptor, whereas IL-5 receptor and GM-CSF receptor mRNA are predominantly increased in chronic AD. These findings support the biphasic role of IL-4, IL-5, and GM-CSF in the pathogenesis of AD skin inflammation. 

---