Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex

Tamada, Taro; Honjo, Eijiro; Maeda, Yoshitake; Okamoto, Tamotsu; Ishibashi, Matsujiro; Tokunaga, Masao; Kuroki, Ryota

doi:10.1073/pnas.0511264103

Cited by 117 publications

(125 citation statements)

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“…However, several cytokine receptors such as gp130 and granulocyte colony-stimulating factor receptor use the extra Ig domain for ligand binding in addition to the cytokine receptor homologous region (15,16). There are several ligand recognition schemes identified for Ig domains of cytokine receptors.…”

Section: Discussionmentioning

confidence: 99%

“…One scheme is generation of a ␤-sheet-like structure by ␤ strands of ligand and receptor, and another is hydrophobic interaction between ligand and receptor. gp130 uses the N and C termini of the Ig domain for generation of a ␤-sheet-like structure and hydrophobic interaction, respectively (15), whereas granulocyte colony-stimulating factor receptor binds to the ligand by hydrophobic interaction via N-and C-terminal portions of the Ig domain (16). The present and previous structural studies show that the ligand recognition manner of the D1 domain of IL-13R␣1 is unique in that the middle portion (residues from 65 to 79) of the D1 domain makes a hydrophobic patch in the ␤-sheet-like structure interfacing with Met-33, Thr-88, Lys-89, Ile-90, and Glu-91 in IL-13 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Distinct Structural Requirements for Interleukin-4 (IL-4) and IL-13 Binding to the Shared IL-13 Receptor Facilitate Cellular Tuning of Cytokine Responsiveness

Ito¹,

Suzuki²,

Kanaji³

et al. 2009

Journal of Biological Chemistry

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Both interleukin-4 (IL-4) and IL-13 can bind to the shared receptor composed of the IL-4 receptor ␣ chain and the IL-13 receptor ␣1 chain (IL-13R␣1); however, the mechanisms by which these ligands bind to the receptor chains are different, enabling the principal functions of these ligands to be different. We have previously shown that the N-terminal Ig-like domain in IL-13R␣1, called the D1 domain, is the specific and critical binding unit for IL-13. However, it has still remained obscure which amino acid has specific binding capacity to IL-13 and why the D1 domain acts as the binding site for IL-13, but not IL-4. To address these questions, in this study we performed mutational analyses for the D1 domain, combining the structural data to identify the amino acids critical for binding to IL-13. Mutations of Lys-76, Lys-77, or Ile-78 in c strand in which the crystal structure showed interaction with IL-13, and those of Trp-65 and Ala-79 adjacent to the interacting site, resulted in significant impairment of IL-13 binding, demonstrating that these amino acids generate the binding site. Furthermore, mutations of Val-35, Leu-38, or Val-42 at the N-terminal ␤-strand also resulted in loss of IL-13 binding, probably from decreased structural stability. None of the mutations employed here affected IL-4 binding. These results demonstrate that the D1 domain of IL-13R␣1 acts as an affinity converter, through direct cytokine interactions, that allows the shared receptor to respond differentially to IL-4 and IL-13.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Distinct Structural Requirements for Interleukin-4 (IL-4) and IL-13 Binding to the Shared IL-13 Receptor Facilitate Cellular Tuning of Cytokine Responsiveness

Ito¹,

Suzuki²,

Kanaji³

et al. 2009

Journal of Biological Chemistry

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“…It contains a conserved cytokine receptor homologous (CRH) domain, an Ig-like domain, and three fibronectin type III-like domains in the extracellular region; a single transmembrane region; and an intracellular region without intrinsic catalytic activity (19,20). Upon G-CSF binding, G-CSFR forms a "crossover," 2:2 ligand:receptor complex, in which each G-CSF molecule binds to both receptors (19,21). Expression of G-CSFR has been detected in both hematopoietic and nonhematopoietic cell types, including the placenta, neurons, endothelial cells, cardiomyocytes, and cancer cells (22).…”

Section: Deregulation Of Neutrophils By the Tumor Microenvironmentmentioning

confidence: 99%

The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis

Liang

Ferrara

2016

Cancer Immunology Research

298

224

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Chronic inflammation fosters cancer development and progression and also modulates tumor responses to anticancer therapies. Neutrophils are key effector cells in innate immunity and are known to play a critical role in various inflammatory disorders. However, the functions of neutrophils in cancer pathogenesis have been largely neglected until recently and still remain poorly characterized compared with other immune cells in the tumor microenvironment. We highlight recent findings on the mechanisms by which tumor cells, in cooperation with tumorassociated stromal cells, induce expansion, recruitment, and polarization of neutrophils. We also review the multifaceted roles that neutrophils play in different aspects of cancer development and progression, with an emphasis on tumor angiogenesis and metastasis.

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“…The cytokines bind to their receptors with high picomolar affinity. This event triggers receptor homodimerization (for example G-CSFR; Horan et al, 1996;Tamada et al, 2006) or heterodimerization/ oligomerization of receptor subunits (for example GM-CSFR; Hayashida et al, 1990) or induces a conformational change in preformed receptor dimers (EPOR; Livnah et al, 1999;Constantinescu et al, 2001) resulting in the activation of the Janus kinases (JAKs). These tyrosine kinases are constitutively associated with cytokine receptors with binding mediated by interactions between the FERM domain of JAK and the Box1 membrane proximal intracytoplasmic region of the receptor.…”

Section: Introductionmentioning

confidence: 99%