Crystal Structure of the Entire Ectodomain of gp130

Xu, Yibin; Kershaw, Nadia J.; Luo, Chu; Soo, Priscilla; Pocock, Michael J.; Czabotar, P.E.; Hilton, Douglas J.; Nicola, Nicos A.; Garrett, T.P.J.; Zhang, Jianguo

doi:10.1074/jbc.c110.129502

Cited by 82 publications

(43 citation statements)

References 38 publications

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“…This result is in agreement with our previous finding that orthotopic inoculation of three different mammary tumor cell lines (one overexpressing Neu) each resulted in larger tumor formation in MKR mice compared to controls (11) (26) and demonstrates that Neu-NT -mediated mammary tumor growth specifically can be enhanced by hyperinsulinemia. The mechanism by which insulin could increase tumor growth in the Neu-NT model may be complex.…”

Section: Discussionsupporting

confidence: 93%

Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

Ferguson¹,

Gallagher²,

Cohen³

et al. 2013

Endocrine-Related Cancer

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The Her2 oncogene is expressed in approximately 25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR+/+) mice were crossed with doxycycline-inducible NeuNT (MTB/TAN) mice to produce the MTB/TAN/MKR+/+ mouse model. Both MTB/TAN and MTB/TAN/MKR+/+ mice were administered doxycycline in drinking water to induce NeuNT mammary tumor formation. In tumor tissues removed at two, four and six weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor (IR)/insulin-like growth factor receptor 1 (IGF-1R), suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no significant further increase in tumor weight was observed in MTB/TAN/MKR+/+ compared to MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+ mice compared to controls (MTB/TAN/MKR+/+ 16.41 ± 4.18 vs. MTB/TAN 5.36 ± 2.72). In tumors at the six week time-point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR+/+ mice resulted in larger primary tumors, with more mesenchymal cells and therefore, more aggressive tumors with more numerous pulmonary metastases.

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Section: Discussionsupporting

confidence: 93%

Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

Ferguson¹,

Gallagher²,

Cohen³

et al. 2013

Endocrine-Related Cancer

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“…These constructs end around residue 300 and, therefore, do not contain the W341 and W356 residues. Hence, we built a homology model of the entire extracellular domain of CSF3R based on the crystal structure of the entire extracellular domain of gp130 (22), which is the structure with the highest sequence homology to CSF3R. Importantly, CSF3R and gp130 have the same domain organization and both belong to the family of tall cytokine receptors.…”

Section: Resultsmentioning

confidence: 99%

Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function

et al. 2017

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Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.

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“…2). The full ectodomain structure of gp130 was solved using X-ray crystallography in 2010 [17] and the structure of domains 1-5 of LIFRβ in 2007 [19]. Although there is no structural information regarding the legs of LIFRβ, the corresponding region of gp130 shows a pronounced kink between the first and second FnIII domains, which in the case of IL-6 and IL-11, can be modelled into existing cryo-EM data [14, 23].…”

Section: Interaction Between Lif and Its Receptormentioning

confidence: 99%

“…On the other hand, the signalling competent complex of LIF with its receptor is a trimer [15] that consists of LIF bound to one molecule of gp130 as well as a second receptor chain called LIFR (LIF receptor-which we will subsequently refer to as LIFRβ) [16] that is architecturally similar to gp130 [17]. Like gp130, LIFRβ binds JAK via its intracellular domain [18] and hence signal transduction can be initiated by transactivation of the gp130-bound and LIFRβ-bound JAK molecules without requiring higher-order association.…”

Section: Introductionmentioning

confidence: 99%

Leukemia inhibitory factor (LIF)

Nicola

Babon

2015

Cytokine & Growth Factor Reviews

Self Cite

341

306

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Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells.

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Crystal Structure of the Entire Ectodomain of gp130

Cited by 82 publications

References 38 publications

Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

Hyperinsulinemia promotes metastasis to the lung in a mouse model of Her2-mediated breast cancer

Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function

Leukemia inhibitory factor (LIF)

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