Taxonomic distribution of proteins containing LIF_OSM domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing LIF_OSM domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding.

Robinson RC, Grey LM, Staunton D, Vankelecom H, Vernallis AB, Moreau JF, Stuart DI, Heath JK, Jones EY
Cell. 1994; 77: 1101-16

The structure of murine leukemia inhibitory factor (LIF) has been determined by X-ray crystallography at 2.0 A resolution. The main chain fold conforms to the four alpha-helix bundle topology previously observed for several members of the hematopoietic cytokine family. Of these, LIF shows closest structural homology to granulocyte colony-stimulating factor and growth hormone (GH). Sequence alignments for the functionally related molecules oncostatin M and ciliary neurotrophic factor, when mapped to the LIF structure, indicate regions of conserved surface character. Analysis of the biological function and receptor specificity of a series of human-mouse LIF chimeras implicate two regions of receptor interaction that are located in the fourth helix and the preceding loop. A model for receptor binding based on the structure of the GH ligand-receptor complex requires additional, novel features to account for these data.

LIF: lots of interesting functions.

Hilton DJ
Trends Biochem Sci. 1992; 17: 72-6

Leukaemia inhibitory factor (LIF) is one of a growing number of cytokines that cannot be readily categorized according to its functions. Rather, these pleiotropic hormones have diverse and often overlapping effects on a multitude of cell types: for example, LIF can inhibit the differentiation of embryonal stem cells on one hand and induce the differentiation of M1 leukaemic cells on the other. Recent work has shed light on the physiological effects of LIF, how these are limited, and the biochemical and biological properties of LIF and its receptor.

Disulfide bond assignment and identification of regions required for functional activity of oncostatin M.

Kallestad JC, Shoyab M, Linsley PS
J Biol Chem. 1991; 266: 8940-5

Oncostatin M is a polypeptide cytokine having unique structure and diverse biological activities, including the ability to inhibit growth of certain cultured tumor cells. Here we have determined the disulfide bonding pattern of recombinant oncostatin M and have used site-directed mutagenesis to identify regions of this molecule necessary for receptor binding and growth inhibitory activities. Two intramolecular disulfide bonds, C6-C127 and C49-C167, were identified in recombinant oncostatin M. Analysis of mutations at each of the five cysteines in oncostatin M indicated that mutants C49S and C167S were inactive (less than 1/10 wild type activity) in growth inhibitory assays and radioreceptor assays. Carboxyl-terminal deletion mutations terminating at S185 and beyond were active, but further shortening abolished activity in both assays. Two deletion mutants proximal to C49 (delta 22-36 and delta 44-47) and insertion mutant GAG77 also were inactive. One deletion mutant, delta 87-90, had significantly (approximately 3-fold) increased activities in both growth inhibitory assays and radioreceptor assays. A potential amphiphilic domain was identified beginning at C167 and extending toward the carboxyl terminus. Two mutants having altered hydrophobic residues within this domain (F176G and F184G) were inactive, suggesting that these residues are required for proper conformation of the receptor binding site. Taken together, these results indicate that biological activity of oncostatin M requires discontinuous regions of the molecule, including residues near the essential disulfide bond, C49-C167, and within a putative amphiphilic helix at the carboxyl terminus. Oncostatin M thus belongs to a growing family of cytokines whose interactions with their respective receptors are mediated in part by known or predicted carboxyl-terminal amphiphilic helices.

Oncostatin M is a member of a cytokine family that includes leukemia-inhibitory factor, granulocyte colony-stimulating factor, and interleukin 6.

Rose TM, Bruce AG
Proc Natl Acad Sci U S A. 1991; 88: 8641-5

Oncostatin M (OSM), a glycoprotein of Mr approximately 28,000 produced by activated monocyte and T-lymphocyte cell lines, was previously identified by its ability to inhibit the growth of cells from melanoma and other solid tumors. We have detected significant similarities in the primary amino acid sequences and predicted secondary structures of OSM, leukemia-inhibitory factor (LIF), granulocyte colony-stimulating factor (G-CSF), and interleukin 6 (IL-6). Analysis of the genes encoding these proteins revealed a shared exon organization, suggesting evolutionary descent from a common ancestral gene. Using a panel of DNAs from somatic cell hybrids, we have shown that OSM, like LIF, is located on human chromosome 22. We have also demonstrated that OSM has the ability to inhibit the proliferation of murine M1 myeloid leukemic cells and can induce their differentiation into macrophage-like cells, a function shared by LIF, G-CSF, and IL-6. We propose that OSM, LIF, G-CSF, and IL-6 are structurally related members of a cytokine family that have in common the ability to modulate differentiation of a variety of cell types.

LIF: a molecule with divergent actions on myeloid leukaemic cells and embryonic stem cells.

Gough NM, Williams RL, Hilton DJ, Pease S, Willson TA, Stahl J, Gearing DP, Nicola NA, Metcalf D
Reprod Fertil Dev. 1989; 1: 281-8

We have previously characterized, purified and cloned a novel murine and human regulator [leukaemia inhibitory factor, LIF] which induces the differentiation of certain murine and human myeloid leukaemic cells. Recently we have shown that there are specific LIF receptors on murine embryonic stem [ES] and embryonal carcinoma [EC] cells and that purified recombinant LIF can substitute for feeder cells and crude sources of differentiation inhibiting activity [DIA] [such as BRL-cell-conditioned medium] in the maintenance of ES cells in a pluripotential state in vitro. Furthermore, ES cells maintained in culture in recombinant LIF for a prolonged period can give rise to germline chimaeric mice. Thus, based on a number of biochemical and biological similarities, it is likely that LIF and DIA are the same molecule. The identification of LIF as a molecule, necessary and sufficient for the maintenance of ES cells in culture, should have a profound impact on the use of these cells for genetic manipulations.