"In addition to helping explain the basic mechanisms of transmembrane receptor signaling, these results may identify a potential therapy for interfering with inflammation," said Michael Karin, Ph.D., professor of pharmacology and pathology in UC San Diego's Laboratory of Gene Regulation and Signal Transduction.
The tumor necrosis factor (TNF) receptor (TNFR) family codes for a large number of cell surface receptors of great biomedical importance, and its signaling mechanisms have been the subject of intense investigation during the past decade. Specific inhibitors of TNF receptor 1 (TNFR1) activation are being used in the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease, and receptor activator of NF-êB (RANK) inhibitors were recently found to be effective in the treatment of osteoporosis and other bone loss diseases.
Now Atsushi Matsuzawa, Ph.D., and Ping-Hui Tseng, Ph.D., postdoctoral fellows in the Karin laboratory, describe how engagement of CD40, a member of the TNFR family, results in assembly of multiprotein signaling complexes at the receptor. However, according to the researchers – and contrary to previous expectations – signaling cascades that lead to activation of Jun Kinases (JNK) and p38 MAP Kinases (MAPK) are not initiated until these complexes dissociate from the receptor.
The authors found that complex translocation from the cell surface receptor to the cytoplasm, which is required for JNK and p38 activation, depends on degradation of a signaling protein called TRAF3. This process can be inhibited by a class of compounds known as Smac mimics.
"As Smac mimic compounds do not interfere with the activation of NF-êB-dependent innate immunity but do prevent the induction of JNK- and p38- dependent inflammatory mediators, they may serve as the prototypes for new anti-inflammatory therapy," said Karin, who also noted that current drugs that work by interfering with TNFR signaling exceed $5 billion a year in revenue.
Debra Kain | EurekAlert!
Cnidarians remotely control bacteria
21.09.2017 | Christian-Albrechts-Universität zu Kiel
Immune cells may heal bleeding brain after strokes
21.09.2017 | NIH/National Institute of Neurological Disorders and Stroke
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
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