26 research outputs found
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State of the structure address on MET receptor activation by HGF
No full textThe MET receptor tyrosine kinase (RTK) and its cognate ligand hepatocyte growth factor (HGF) comprise a signaling axis essential for development, wound healing and tissue homeostasis. Aberrant HGF/MET signaling is a driver of many cancers and contributes to drug resistance to several approved therapeutics targeting other RTKs, making MET itself an important drug target. In RTKs, homeostatic receptor signaling is dependent on autoinhibition in the absence of ligand binding and orchestrated set of conformational changes induced by ligand-mediated receptor dimerization that result in activation of the intracellular kinase domains. A fundamental understanding of these mechanisms in the MET receptor remains incomplete, despite decades of research. This is due in part to the complex structure of the HGF ligand, which remains unknown in its full-length form, and a lack of high-resolution structures of the complete MET extracellular portion in an apo or ligand-bound state. A current view of HGF-dependent MET activation has evolved from biochemical and structural studies of HGF and MET fragments and here we review what these findings have thus far revealed
Author Correction: Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands
No full textAuthor response: Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling
No full textMapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning
No full textMutations in the kinase and juxtamembrane domains of the MET Receptor Tyrosine Kinase are responsible for oncogenesis in various cancers and can drive resistance to MET-directed treatments. Determining the most effective inhibitor for each mutational profile is a major challenge for MET-driven cancer treatment in precision medicine. Here, we used a deep mutational scan (DMS) of ~5764 MET kinase domain variants to profile the growth of each mutation against a panel of 11 inhibitors that are reported to target the MET kinase domain. We validate previously identified resistance mutations, pinpoint common resistance sites across type I, type II, and type I ½ inhibitors, unveil unique resistance and sensitizing mutations for each inhibitor, and verify non-cross-resistant sensitivities for type I and type II inhibitor pairs. We augment a protein language model with biophysical and chemical features to improve the predictive performance for inhibitor-treated datasets. Together, our study demonstrates a pooled experimental pipeline for identifying resistance mutations, provides a reference dictionary for mutations that are sensitized to specific therapies, and offers insights for future drug development
Structure and Functional Characterization of the Conserved JAK Interaction Region in the Intrinsically Disordered N‑Terminus of SOCS5
No full textSOCS5
can negatively regulate both JAK/STAT and EGF-receptor pathways
and has therefore been implicated in regulating both the immune response
and tumorigenesis. Understanding the molecular basis for SOCS5 activity
may reveal novel ways to target key components of these signaling
pathways. The N-terminal region of SOCS5 coordinates critical protein
interactions involved in inhibition of JAK/STAT signaling, and a conserved
region within the N-terminus of SOCS5 mediates direct binding to the
JAK kinase domain. Here we have characterized the solution conformation
of this conserved JAK interaction region (JIR) within the largely
disordered N-terminus of SOCS5. Using nuclear magnetic resonance (NMR)
chemical shift analysis, relaxation measurements, and NOE analysis,
we demonstrate the presence of preformed structural elements in the
JIR of mouse SOCS5 (mSOCS5<sub>175–244</sub>), consisting of
an α-helix encompassing residues 224–233, preceded by
a turn and an extended structure. We have identified a phosphorylation
site (Ser211) within the JIR of mSOCS5 and have investigated the role
of phosphorylation in modulating JAK binding using site-directed mutagenesis
Suppressor of Cytokine Signaling (SOCS) 5 Utilises Distinct Domains for Regulation of JAK1 and Interaction with the Adaptor Protein Shc-1
No full textSuppressor of cytokine signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1
No full textSuppressor 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 region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling
Key Role of Suppressor of Cytokine Signaling 3 in Regulating gp130 Cytokine–Induced Signaling and Limiting Chondrocyte Responses During Murine Inflammatory Arthritis
No full textSuppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling
No full textInfluenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.</p
