LIF receptor

Figure 8.1 Cytokine receptors usually display a unique cytokine ( ligand )-binding domain, but they share additional receptor components that are normally responsible for signal transduction. This explains the molecular basis of pleiotropy. IL-6, IL-11 and LIF receptors, for example, are all composed of a distinct ligand-specific binding domain and a separate subunit (gp 130). gp 130 is responsible for initiating signal transduction and is identical in all three receptors. This is depicted schematically above...

LIF receptor also uses its Ig domain (D3) to receive site III epitopes of GNTF, LIF, GT-1, OSM, and others. So the Ig domain of LIF receptor is, in fact, more cross-reactive than gplSO. The site III structures of all gp 130-cytokines maintain a conserved aromatic residue at the tip of the D helix (Fig. 7) that is certainly the structural analog to the Trp residues we see in the center of the gplSO site III interface. Therefore we predict that the LIFR site III interface cross-reactivity is achieved by using similar structural features at the gplSO IgD. 

Aasland, D., Oppmann, B., Grotzinger, J., Rose-John, S., and Kallen, K. J. (2002). The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex. J. Mol. Biol. 315, 637-646. 

Plun-Favreau, H., Ferret, D., Diveu, C., Froger, J., Chevalier, S., Lelievre, E., Gascan, H., and Chabbert, M. (2003). Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor./. Biol. Chem. 278, 27169-27179. 

Cytokine receptors sometimes need auxiliary factors and co-receptors. An example is the LIF-receptor-a (LIFR-a), a t e I cjdiokine receptor which requires LIFR-P as co-receptor for signalling. 

Butzkueven H, Zhang JG, Hanninen MS, Hochrein H, Chionh F, Shipham KA, Emery B, Tumley AM, Petratos S, Ernst M, Bartlett PF, BHlpatrick TJ (2002) LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nat Med 8 613-619. 

D. K. Smith, H. R. Treutlein. LIF receptor-gpl30 interaction investigated by homology modeling implications for LIF binding. Protein Sci. 1998, 7, 886-896. 

In contrast to mice which lack CNTF, CNTFRa knockout mice die perinatally, and display severe motor neuron deficits (DeChiara et al., 1995). Similarly, mice that lack the common signal transducer gpl30 display embryonic lethality and have diverse embryonic defects (Yoshida et al., 1993), while mice that lack the shared LIF receptor die in the perinatal development period and exhibit placental, skeletal, neural and metabolic defects (Li et al., 1995 Ware et al., 1995). 

Although some researchers are still cautious to accept some of these activities as in vivo functions, a substantial amount of data has now become available to enable evaluation of recent findings. To better understand the pleiotropic nature of LIF, structural analysis of LIF receptors and studies of its signal transduction are essential. 

The LIF receptor complex consists of gpl30 and LIF-R. Since the heterodimer complex of gpl30 and LIF-R functions as a receptor for OSM as well, the two factors exhibit in general very similar activities in vitro. If a cell also expresses the CNTF-R(a) receptor, CNTF should induce similar effects to those induced by LIF and OSM. Thus, the activities in vitro exhibited by the members of the IL-6 family overlap. In fact, this is one of the reasons why we see such multiple in vitro activities of LIF, as described in Section 2. 

Pregnancy associated increase in mRNA for soluble D-factor/ LIF receptor in mouse liver. FEBS Lett. 334 193-197. 

Three different cDNAs encoding mouse D-factor/LiF receptor. J. Biochem. 115 557-562. 

IL-6 family of cytokines that is known primarily for its effects on cell growth. Human OCM shows 25% sequence homology with leukemia inhibitory factor (LIF). Both share a functional high-affinity receptor that is composed of gpl30 and a LIF receptor subunit. OSM is well known for its function in infiaramation, cell proliferation, and hematopoiesis. Furthermore, OSM induces potent growth-inhibitory and morphogenic responses in several different tumor cell types [T. M. Rose, A. G. Bruce, Proc. Natl. Acad. Sci. USA 1991, 88, 8641 ... 

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