About
424
Publications
25,205
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
38,397
Citations
Introduction
Skills and Expertise
Publications
Publications (424)
Thrombopoietin (Tpo), which binds to its specific receptor, the Mpl protein, is the major cytokine regulator of megakaryopoiesis and circulating platelet number. Tpo binding to Mpl triggers activation of Janus kinase 2 (Jak2) and phosphorylation of the receptor, as well as activation of several intracellular signalling cascades that mediate cellula...
Thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers and is required for haematopoetic stem cell maintenance. Tpo functions by binding its receptor (TpoR, a homodimeric Class I cytokine receptor) and initiating cell proliferation or differentiation. Here we characterise the murine Tpo:TpoR signalling complex biochemic...
Protein Tyrosine Phosphatase 1B (PTP1B) is the prototypical protein tyrosine phosphatase and plays an essential role in the regulation of several kinase-driven signalling pathways. PTP1B displays a preference for bisphosphorylated substrates. Here we identify PTP1B as an inhibitor of IL-6 and show that, in vitro, it can dephosphorylate all four mem...
Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and st...
Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and st...
The JAK–STAT pathway is the central intracellular signal transduction cascade initiated by ligand binding to numerous growth factor and cytokine receptors, and since its discovery two decades ago it has been the subject of extensive investigation. The pathway is negatively regulated by the SOCS family proteins, which restrict the extent of the cyto...
Dendritic cells (DC) use a variety of cell surface receptors to monitor the environment for potential dangers, including cells that have died of non-homeostatic causes (eg. infected cells), to induce appropriate immune responses. Clec9A is a DC-specific Damage-Associated Molecular Pattern receptor, that is expressed by mouse and human cross-present...
MARCH proteins are membrane‐associated Ring‐CH E3 ubiquitin ligases that dampen immune responses by down‐regulating cell surface expression of major histocompatibility complexes I and II as well as immune co‐stimulatory receptors. We recently showed that MARCH2,3,4 and 9 also down‐regulate cell surface expression of the inflammatory cytokine recept...
The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8 ⁺ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique propertie...
Janus kinases (JAKs) are found constitutively associated with cytokine receptors and are present in an inactive state prior to cytokine exposure. Activating mutations of JAKs are causative for a number of leukemias, lymphomas, and myeloproliferative diseases. In particular, the JAK2V617F mutant is found in most human cases of polycythemia vera, a d...
Interleukin 6 (IL6) is a cytokine that regulates a number of important immune and inflammatory pathways. We used the ability of IL6 to inhibit the clonal proliferation of the mouse M1 myeloid leukemia cell line in agar to positively screen a cDNA expression library for proteins that inhibited IL6 activity. We found three clones completely resistant...
Constitutive activation of the Jak/Stat signalling pathway is a hallmark of Myeloproliferative Neoplasms (MPN), with 60-90% of patients carrying the activating JAK2 mutation, JAK2V617F. Several studies suggest expression of a type I cytokine receptor is essential for JAK2V617F-mediated transformation, but the precise contribution of such receptors...
The innate immune system is our first line of defence against viral pathogens. Host cell pattern recognition receptors (PRRs) sense viral components and initiate immune signalling cascades that result in the production of an array of cytokines to combat infection. The retinoic acid inducible gene‐I (RIG‐I) is a PRR that recognises viral RNA and, wh...
Background
Constitutive activation of the Jak/Stat signalling pathway is a hallmark of Myeloproliferative Neoplasms (MPN), with 60–90% of patients carrying the activating JAK2 mutation, JAK2 V617F . Several studies suggest expression of a type I cytokine receptor is essential for JAK2 V617F ‐mediated transformation, but the precise contribution of...
The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structur...
The retinoic acid-inducible gene-I (RIG-I) receptor recognizes short 5'-di and triphosphate base-paired viral RNA and is a critical mediator of the innate immune response against viruses such as influenza A, ebola, HIV and hepatitis C. This response is reported to require an orchestrated interaction with the tripartite motif 25 (TRIM25) B30.2 prote...
The Hematopoietically-expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment...
The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and S...
Experimental design for generation and analysis of mice lacking both SOCS1 and SOCS3 within the hematopoietic system.
(A) Generation of mice lacking SOCS1, SOCS3 or both in the hematopoietic system. Experimental mice were highly reconstituted (>80% CD45.2+) wild-type recipients of bone marrow from the specific donor genotypes indicated that were su...
Interleukin-6 signalling in mice lacking SOCS proteins.
Original uncropped western blots of protein lysates from macrophages prepared from mice 14d after tamoxifen or vehicle treatment. The cells were stimulated with IL-6 for the times indicated. Proteins were separated by polyacrylamide gel electrophoresis, transferred to membranes and probed with...
Cytokine signalling in mice lacking SOCS proteins.
Representative flow cytometry profiles of PhosFlow measurement of phosphorylated STAT3 (A) and STAT5 (B) in granulocytes prepared from mice 14d after tamoxifen or vehicle treatment. Cells were stimulated with G-CSF (A) or GM-CSF (B) for the times indicated.
(TIF)
Altered bone marrow granulocyte and spleen T cell numbers and pathology in mice lacking SOCS1 and/or SOCS3.
Representative flow cytometry profiles from analysis of (A) neutrophils (Gr-1+ CD11b+) in the spleen, bone marrow and blood or (B) CD8+ T cells in the spleens of mice at 50 days following tamoxifen or vehicle treatment, or upon signs of disea...
Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR): glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR):glycoprotein 130 (gp130) hetero...
Donald Metcalf was one of Australia's most distinguished medical researchers and is acknowledged internationally as the father of the modern field of haemopoietic growth factors. He defined the hierarchy of haemopoietic progenitor cells, purified and cloned the major molecular regulators of their growth and maturation, determined their mechanisms o...
The JAK–STAT pathway is the central intracellular signal transduction cascade initiated by ligand binding to numerous growth factor and cytokine receptors, and since its discovery two decades ago it has been the subject of extensive investigation. The pathway is negatively regulated by the SOCS family proteins, which restrict the extent of the cyto...
A collection of tributes and remembrances from esteemed colleagues, mentees, and friends on the life and work of "the father of hematopoietic cytokines".
Mutations of the reelin gene cause severe defects in cerebral cortex development and profound intellectual impairment. While many aspects of the
reelin signaling pathway have been identified, the molecular and ultimate cellular consequences of reelin signaling remain
unknown. Specifically, it is unclear if termination of reelin signaling is as impo...
The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Trophoblast cell proliferation, migration and invasion into the endometrium are fundamental events in the initiation of placentation. Leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasio...
The placenta forms the interface between the maternal and fetal circulation and is critical for the establishment of a healthy pregnancy. Specialized trophoblast cells derived from the embryonic trophectoderm play a pivotal role in the establishment of the placenta. Leukemia inhibitory factor (LIF) is one of the predominant cytokines present in the...
Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. Mice lacking functional SOCS4 are hypersusceptible to primary infection with influenza A virus (IAV), displaying dysregulated pro-inflammatory cytokine and chemokine production in the lungs, delayed viral clearance and impaired trafficking of influe...
The suppressors of cytokine signaling (SOCS) family of proteins act as intracellular inhibitors of several cytokine signal transduction pathways. Their expression is induced by cytokine activation of the Janus kinase signal transducer and activator of transcription (JAKSTAT) pathway and they act as a negative feedback loop by subsequently inhibitin...
We have expressed and purified three soluble fragments of the human LRIG1extracellular domain (ECD): the LRIG1-LRR (Leucine-rich repeat) domain, the LRIG1-3Ig (Immunoglobulin-like) domain, and the LRIG1-LRR-1Ig fragment using baculovirus vectors in insect cells. The two LRIG1 domains crystallized, so that we have been able to determine the 3D-struc...
Once more unto the breach, dear friends, once more,Or close the wall up with our English dead!In peace there’s nothing so becomes a manAs modest stillness and humility,But when the blast of war blows in our ears,Then imitate the action of the tiger:Stiffen the sinews, summon up the blood.—William Shakespeare (King Henry, Henry V)
Donald Metcalf was one of the world’s leading experimental hematologists. His discoveries in the fields of colony stimulating factors, cell signaling, and blood cell development not only established many of the concepts of modern hematology but also led to revolutions in the treatment of patients undergoing chemotherapy and bone-marrow transplants,...
SPRY/B30.2 domain-containing proteins are found in 103 human proteins that regulate numerous cellular processes including RNA processing, histone methylation, red blood cell membrane integrity, terminal erythroid cell differentiation and innate immune responses. Despite an increased understanding of SPRY/B30.2 domain function, some confusion remain...
Maintenance of the haematopoietic and immune systems is largely controlled by the secretion of cytokines. Cytokine exposure initiates an intracellular signalling cascade that is driven by activation of a family of receptor-bound tyrosine kinases known as the JAKs (Janus Kinases). Under physiological conditions, JAK activation and signalling is tigh...
Protein kinases play a key role in numerous cell signaling pathways. They have emerged as an important class of enzymes since aberrant kinase activity is associated with human diseases such as cancer and inflammatory disorders such as rheumatoid arthritis. While the human kinome is comprised of over 500 members, only a fraction have been exploited...
The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still be...
Author Summary
The suppressor of cytokine signaling proteins are key regulators of immunity. As yet there is no described biological role for SOCS4, despite its broad expression in cells of the immune system. Given the important role of other SOCS proteins in controlling the immune response, we have generated SOCS4-mutant mice and used a mouse infl...
Abstract Activation of the cell surface receptor, c-Mpl, by the cytokine, thrombopoietin (TPO), underpins megakaryocyte and platelet production in mammals. In humans, mutations in c-Mpl have been identified as the molecular basis of Congenital Amegakaryocytic Thrombocytopenia (CAMT). Here, we show that CAMT-associated mutations in c-Mpl principally...
Abstract SOCS3 (suppressor of cytokine signaling 3) inhibits the intracellular signaling cascade initiated by exposure of cells to cytokines. SOCS3 regulates signaling via two distinct mechanisms: directly inhibiting the catalytic activity of Janus kinases (JAKs) that initiate the intracellular signaling cascade and catalysing the ubiquitination of...
IL-6 a multi-functional cytokine with important effects in both inflammation and haematopoiesis. SOCS3 is the primary inhibitor of IL-6 signalling, interacting with gp130, the common shared chain of the IL-6 family of cytokines, and JAK1, JAK2 and TYK2 to control both the duration of signalling and the biological response. Recent biochemical and st...
JAK2 (Janus kinase 2) initiates the intracellular signalling cascade downstream of cell surface receptor activation by cognate haematopoietic cytokines, including erythropoietin and thrombopoietin. The pseudokinase (JH2) domain of JAK2 negatively regulates the catalytic activity of the adjacent tyrosine kinase (JH1) domain and mutations within the...
SOCS3 is an inducible negative feedback inhibitor of cytokine signaling. Conditional deletion of SOCS3 in mice using the Cre-lox system has now been applied to a range of cell types in the steady-state and under inflammatory, pathogenic, or tumorigenic stress, with the resulting phenotypes demonstrating the effects of SOCS3 in physiological and dis...
Tripartite motif (TRIM) proteins primarily function as ubiquitin E3 ligases that regulate the innate immune response to infection. TRIM25 (also known as estrogen-responsive finger protein (Efp)) has been implicated in the regulation of estrogen receptor α signaling, and in the regulation of innate immune signaling via retinoic acid-inducible gene-I...
Mixed lineage kinase domain-like (MLKL) is a component of the "necrosome," the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice w...
Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved re...
Suppressor of cytokine signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1.
(DOCX)
JAKs (Janus kinases) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines. However, aberrant and/or prolonged JAK-induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies. For this reason, the tyrosine kinase activity of the JAKs is car...
To study the effect of polyethylene glycated leukemia inhibitory factor (LIF) antagonist (PEGLA) in the human blastocyst viability and implantation process.
In vitro study.
University hospital and research laboratory.
Endometrial biopsy samples from fertile donors (n = 20), and surplus, frozen, good-quality human embryos obtained from an in vitro f...
This review focuses on contributions to cytokine biology made by Australians in Australia. It is clearly biased by my own experiences and selective recollections especially related to the colony-stimulating factors in which Australian involvement has been pre-eminent from discovery to clinical use. Nevertheless Australian scientists have also made...
The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between mouse SOCS3, JAK2 (kinase...
Gene deletion studies in mice have revealed critical roles for interleukins-4 and -13 in asthma development, with the latter controlling lung airways resistance and mucous secretion. We have now developed human neutralizing monoclonal antibodies against the human IL-13 receptor α1 subunit that prevent activation of the receptor complex by both IL-4...
The SPRY domain is a protein interaction module found in 77 murine and approximately 100 human proteins, and is implicated in important biological pathways, including those that regulate innate and adaptive immunity. The current definition of the SPRY domain is based on a sequence repeat discovered in the splA kinase and ryanodine receptors. The gr...
The receptor-associated JAK protein kinases and their substrates, the STAT transcriptional activators, transmit signals following cytokine and growth factor binding to receptors expressed on the cell surface, to result in specific transcriptional and cellular responses. Over the last two decades, the field has progressed from identification of the...
Synthetic CpG oligonucleotides (ODN) have potent immunostimulatory properties exploited in clinical vaccine trials. How CpG ODN are captured and delivered to the intracellular receptor TLR9, however, has been elusive. Here we show that DEC-205, a multilectin receptor expressed by a variety of cells, is a receptor for CpG ODN. When CpG ODN are used...
Suppressors of cytokine signaling 3 (SOCS3) has been shown to be an important and non-redundant feedback inhibitor of several cytokines including leukemia inhibitory factor, IL-6, IL-11, Ciliary neurotrophic factor (CNTF), leptin, and granulocyte colony-stimulating factor (G-CSF). Loss of SOCS3 in vivo has profound effects on placental development,...
The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated...
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (suppressor of cytokine signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2, and TYK2...
Neutrophils are constitutively produced throughout adult life and are essential for host responses to many types of pathogen. Neutropenia has long been associated with poor prognosis in the clinic, yet we have an incomplete understanding of their life cycle, not only during homeostasis but also during infection and chronic inflammation. Here, we re...
Inhibition of LIF-induced proliferation of Ba/F3 cells expressing human LIFR and IL6ST by PEGLA. The maximum possible value for cell number in this assay was 200. •, PEGLA (19); ▪, PEGLA (this study).
(JPG)
Tissue accumulation of 125I-PEGLA and 125I-PEGBSA at 2 h (A) and 24 h (B) following IP injection. Thyroid accumulation not shown due to scale. There was no difference in thyroid accumulation between the 3 groups. ▪, 125I-PEGBSA non-mated; ▪, 125I-PEGLA non-mated; □ 125I-PEGLA mated. *, significant difference (P<0.05).
(JPG)
Tissue accumulation of 125I in the 24 h following vaginal application. •, 125I-PEGLA non-mated; ▪, 125I-PEGLA mated; ◊, 125I-PEGBSA non-mated.
(JPG)
Tissue accumulation of 125I-PEGLA normalized to administered dose in the 24 h following IP injection ▪ and vaginal application ▪ 125I-PEGLA counts have been normalised to the total 125I-PEGLA counts administered (%AD, % administered dose) to allow a comparison between the two delivery routes. *, significant difference (P<0.05).
(JPG)
Localization of PEGLA and inhibition of implantation following vaginal application of PEGLA in CAPRISA 400 gel (1∶2 dilution) to mated mice. A–D. PEGLA localization in the uterine luminal (A&C) and glandular epithelium (B&D), at 3 h (A&C) and 24 h (B&D) following vaginal application PEGLA. Arrows indicate positive staining for PEGLA. Insert, negati...
Tissue accumulation of 125I in the 120 h following IP injection. •, 125I-PEGLA non-mated; ▪, 125I-PEGLA mated; ◊, 125I-PEGBSA non-mated.
(JPG)
A. Circulating protein bound (TCA-precipitable) 125I in the 120 h following IP injection. B. Percentage of total 125I counts in blood that are protein bound (TCA-precipitable) in the 120 h following IP injection. C. Circulating protein bound (TCA-precipitable) 125I in the 96 h following vaginal application. D. Percentage of total 125I counts in blo...
Tissue accumulation of 125I-PEGLA and 125I-PEGBSA at 2 h (A) and 24 h (B) following vaginal application. Thyroid accumulation not shown due to scale. There was no difference in thyroid accumulation between the 3 groups. ▪, 125I-PEGBSA non-mated; ▪, 125I-PEGLA non-mated; □ 125I-PEGLA mated. *, significant difference (P<0.05).
(JPG)
Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF) is obligatory for blastocyst implantation in mice...
The lack of expression of the suppressor of cytokine signalling-3 (SOCS3) or inactivation of the negative regulatory capacity of SOCS3 has been well documented in rheumatoid arthritis, viral hepatitis and cancer. The specific qualitative and quantitative consequences of SOCS3 deficiency on interleukin-6 (IL-6)-mediated pro- and anti-inflammatory re...
With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid met...
gp130 is the shared signal-transducing receptor subunit for the large and important family of interleukin 6-like cytokines.
Previous x-ray structures of ligand-receptor complexes of this family lack the three membrane-proximal domains that are essential
for signal transduction. Here we report the crystal structure of the entire extracellular portio...
gp130 is the shared signal-transducing receptor subunit for the large and important family of interleukin 6-like cytokines.
Previous x-ray structures of ligand-receptor complexes of this family lack the three membrane-proximal domains that are essential
for signal transduction. Here we report the crystal structure of the entire extracellular portio...
Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteobla...
Suppressor of cytokine signalling (SOCS) 3 is an essential regulator of cytokine signalling, and in turn its expression is tightly regulated. Data from overexpression studies in cell lines suggest that SOCS2 regulates SOCS3 protein degradation, by forming a molecular bridge to an E3 ubiquitin-ligase complex. Whether this regulation is relevant in p...
Uterine leukaemia inhibitory factor (LIF) is obligatory for fertility in mice and associated with infertility in women. Intraperitoneal injection (IPI) of a long-acting LIF inhibitor conjugated to polyethylene glycol (PEGLA) blocks endometrial LIF action preventing implantation¹. Thus, PEGLA is a promising non-hormonal contraceptive. In women, vagi...
The SOCS (suppressors of cytokine signalling) family of proteins inhibits the cytokine-induced signalling cascade in part by promoting the ubiquitination of signalling intermediates that are then targeted for proteasomal degradation. This activity relies upon an interaction between the SOCS box domain, the adapter complex elonginBC and a member of...
The mechanism by which Suppressor of Cytokine Signaling-3 (SOCS3) negatively regulates cytokine signaling has been widely investigated using over-expression studies in cell lines and is thought to involve interactions with both the gp130 receptor and JAK1. Here, we compare the endogenous JAK/STAT signaling pathway downstream of Leukemia Inhibitory...
