48 research outputs found
The beta c receptor family - Structural insights and their functional implications
No full textAbstract not availableSophie E. Broughton, Tracy L. Nero, Urmi Dhagat, Winnie L. Kan, Timothy R. Hercus, Denis Tvorogov, Angel F. Lopez, Michael W. Parke
Conformational changes in the GM-CSF receptor suggest a molecular mechanism for affinity conversion and receptor signaling
No full textAbstract not availableSophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Mara Dottore, Barbara J. McClure, Urmi Dhagat, Houng Taing, Michael A. Gorman, Jack King-Scott, Angel F. Lopez, Michael W. Parke
Cytokine receptor activation at the cell surface
No full textCytokines are well recognized for the pleiotropic nature of their signaling and biological activities on many cell types and their role in health and disease. Recent years have seen a steady stream of new cytokine receptor crystal structures including those that are activated by GM-CSF, type I interferon, and a variety of interleukins. Highlights include the observation of a dodecameric signaling complex for the GM-CSF receptor, electron microscopy imaging of an intact gp130/IL-6/IL-6Rα ternary receptor complex bound to its signal transducing Janus kinase and visualization of novel cytokine recognition mechanisms in the interleukin-17 and type I interferon families. This increasing knowledge in cytokine structural biology is driving new opportunities for developing novel therapies to modulate cytokine function in a diverse range of diseases including malignancies and chronic inflammation.Sophie E Broughton, Timothy R Hercus, Angel F Lopez and Michael W Parke
Signalling by the beta c family of cytokines
No full textThe GM-CSF, IL-3 and IL-5 family of cytokines, also known as the βc family due to their receptors sharing the signalling subunit βc, regulates multiple biological processes such as native and adaptive immunity, inflammation, normal and malignant hemopoieis, and autoimmunity. Australian scientists played a major role in the discovery and biological characterisation of the βc cytokines and their recent work is revealing unique features of cytokine receptor assembly and signalling. Furthermore, specific antibodies have been generated to modulate their function. Characterisation of the structural and dynamic requirements for the activation of the βc receptor family and the molecular definition of downstream signalling pathways are providing new insights into cytokine receptor signalling as well as new therapeutic opportunities.Timothy R. Hercus, Urmi Dhagat, Winnie L.T. Kan, Sophie E. Broughton, Tracy L. Nero, Michelle Perugini, Jarrod J. Sandow, Richard J. D’Andrea, Paul G. Ekert, Timothy Hughes, Michael W. Parker, Angel F. Lope
Messing with beta c: a unique receptor with many goals
No full textOur understanding of the biological role of the βc family of cytokines has evolved enormously since their initial identification as bone marrow colony stimulating factors in the 1960's. It has become abundantly clear over the intervening decades that this family of cytokines has truly astonishing pleiotropic capacity, capable of regulating not only hematopoiesis but also many other normal and pathological processes such as development, inflammation, allergy and cancer. As noted in the current pandemic, βc cytokines contribute to the cytokine storm seen in acutely ill COVID-19 patients. Ongoing studies to discover how these cytokines activate their receptor are revealing insights into the fundamental mechanisms that give rise to cytokine pleiotropy and are providing tantalizing glimpses of how discrete signaling pathways may be dissected for activation with novel ligands for therapeutic benefit.Winnie L. Kan, Karen S. Cheung Tung Shing, Tracy L. Nero, Timothy R. Hercus, Denis Tvorogov, Michael W. Parker, Angel F. Lope
Crystallization and preliminary X-ray diffraction analysis of the interleukin-3 alpha receptor bound to the Fab fragment of antibody CSL362
No full textInterleukin-3 (IL-3) is a member of the beta common family of cytokines that regulate multiple functions of myeloid cells. The IL-3 receptor-specific alpha subunit (IL3Rα) is overexpressed on stem cells/progenitor cells of patients with acute myeloid leukaemia, where elevated receptor expression correlates clinically with a reduced patient survival rate. The monoclonal antibody (MAb) CSL362 is a humanized MAb derived from the murine MAb 7G3, originally identified for its ability to specifically recognize the human IL-3 receptor and for blocking the signalling of IL-3 in myeloid and endothelial cells. In order to elucidate the molecular mechanism of CSL362 antagonism, a preliminary structure of human IL3Rα in complex with the MAb CSL362 has been determined.Sophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Urmi Dhagat, Catherine M. Owczarek, Matthew P. Hardy, Louis J. Fabri, Pierre D. Scotney, Andrew D. Nash, Nicholas J. Wilson, Angel F. Lopez and Michael W. Parkera
The GM-CSF receptor family: mechanism of activation and implications for disease
No full textGranulocyte-macrophage colony-stimulating factor (GM-CSF) is a pluripotent cytokine produced by many cells in the body, which regulates normal and malignant hemopoiesis as well as innate and adaptive immunity. GM-CSF assembles and activates its heterodimeric receptor complex on the surface of myeloid cells, initiating multiple signaling pathways that control key functions such as cell survival, cell proliferation, and functional activation. Understanding the molecular composition of these pathways, the interaction of the various components as well as the kinetics and dose-dependent mechanics of receptor activation provides valuable insights into the function of GM-CSF as well as the related cytokines, interleukin-3 and interleukin-5. This knowledge provides opportunities for the development of new therapies to block the action of these cytokines in hematological malignancy and chronic inflammation.Timothy R. Hercus, Sophie E. Broughton, Paul G. Ekert,Hayley S. Ramshaw, Michelle Perugini, Michele Grimbaldeston, Joanna M. Woodcock, Daniel Thomas, Stuart Pitson, Timothy Hughes, Richard J. D’andrea, Michael W. Parker, & Angel F. Lope
Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit
No full textGranulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, βc, with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated βc mutants that display distinct signaling capacity and have differential requirements for the GMR {alpha}-subunit (GMR-{alpha}) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FI{Delta}) selectively activates the phosphoinositide 3-kinase/Akt and I{kappa}Kβ/nuclear factor{kappa}B pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-{alpha} and show a selective requirement for Src family kinases by the FI{Delta} mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex.Michelle Perugini, Anna L. Brown, Diana G. Salerno, Grant W. Booker, Cvetan Stojkoski, Timothy R. Hercus, Angel F. Lopez, Margaret L. Hibbs, Thomas J. Gonda, and Richard J. D'Andre
Translating the biology of B common receptor-engaging cytokines into clinical medicine
No full textThe family of cytokines that comprises IL-3, IL-5, and GM-CSF was discovered over 30 years ago, and their biological activities and resulting impact in clinical medicine has continued to expand ever since. Originally identified as bone marrow growth factors capable of acting on hemopoietic progenitor cells to induce their proliferation and differentiation into mature blood cells, these cytokines are also recognized as key mediators of inflammation and the pathobiology of diverse immunologic diseases. This increased understanding of the functional repertoire of IL-3, IL-5, and GM-CSF has led to an explosion of interest in modulating their functions for clinical management. Key to the successful clinical translation of this knowledge is the recognition that these cytokines act by engaging distinct dimeric receptors and that they share a common signaling subunit called β-common or βc. The structural determination of how IL-3, IL-5, and GM-CSF interact with their receptors and linking this to their differential biological functions on effector cells has unveiled new paradigms of cell signaling. This knowledge has paved the way for novel mAbs and other molecules as selective or pan inhibitors for use in different clinical settings.Harshita Pant, Timothy R. Hercus, Damon J. Tumes, Kwok Ho Yip, Michael W. Parker, Catherine M. Owczarek, Angel F. Lopez, and David P. Husto
The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling
No full textGranulocyte–macrophage colony-stimulating factor (GM– CSF), interleukin-3 (IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM–CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation.
Together with a wealth of associated structure–function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM–CSF/IL-3/IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease.Sophie E. Broughton, Urmi Dhagat, Timothy R. Hercus, Tracy L. Nero, Michele A. Grimbaldeston, Claudine S. Bonder, Angel F. Lopez, Michael W. Parke
