CD28, which colocalizes with the TCR in the immune synapse, is a well-studied costimulatory protein; the mechanism whereby CD28 transmits costimulatory signals to T cells, however, remains controversial. Okkenhaug nominated a pair of papers that shed light on the role of RLTPR (RGD, leucine-rich repeat, tropomodulin, and proline-rich–containing protein), a cytosolic protein previously implicated in CD28 signaling () showed that RLTPR acts as an adaptor to link the CD28 C-terminal to the CARD11/CARMA1 complex and activation of nuclear factor κB (NF-κB), a transcription factor stimulated in activated T cells. Okkenhaug noted, “More work is needed to map the precise molecular interactions, but this body of work finally defines a unique CD28-dependent signaling pathway in T cells.”A deeper understanding of the signaling pathways by which cancer cells evade destruction by the immune system can be expected to lead to more effective approaches to cancer immunotherapy. One such mechanism involves the interaction between PD-1 (programmed cell death protein 1), a receptor found on T cells, and PD-L1 (programmed death ligand 1), found on macrophages and dendritic cells, as well as various cancer cells. Canals, Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling. The final neuroscience-themed nomination, from Hell, concerned an intriguing twist on the mechanisms underlying long-term depression (LTD) of synaptic transmission in the CA1 region of the hippocampus ().
In addition to providing insight into the physiological role of Pr P) both used computational approaches to discover either new drugs targeting the opioid receptor (A) or a new mechanism of inhibition of the kinase GSK-3 (B).
[Panel (A) is reprinted with permission from ) both used computational approaches to discover either new drugs targeting the opioid receptor (A) or a new mechanism of inhibition of the kinase GSK-3 (B).
More specifically, this year’s breakthroughs include studies of ligand-receptor interactions, an unexpected mechanism of synaptic plasticity, a unique way to inhibit a kinase, insight into the consequences of cellular nutrient deprivation, and a quantitative analysis of the mitochondrial metabolome.
Perhaps reflecting the growing maturity of the discipline of cellular signal transduction, many of this year’s nominations are relevant to the pathogenesis or have application to the treatment of human disease. Reth, B cell antigen receptors of the Ig M and Ig D classes are clustered in different protein islands that are altered during B cell activation.
Like other protein kinases, however, developing an inhibitor that is both potent and selective has been a challenge.
Kinase inhibitors that target the adenosine 5′-triphosphate (ATP) binding site tend to lack specificity, whereas competitive inhibitors derived from kinase substrates tend to be weak. Signaling breakthroughs of 2016 clustered mainly in the areas of neuroscience, immunology, and metabolism, with excursions into plant hormone signaling and bacterial manipulation of host signaling pathways. Perhaps reflecting the growing maturity of the discipline of cell signaling, many of this year’s breakthroughs have implications for the pathogenesis or treatment of human disease. The 2016 nominations clustered mainly in the areas of neuroscience, immunology, and cellular metabolism, with intriguing excursions into mechanisms of plant hormone receptor signaling and bacterial manipulation of host cell signaling pathways. Moreover, PZM21 did not cause respiratory depression or addiction-like behaviors. Dohlman’s second nomination concerned a study identifying the cellular prion protein Pr P acted as a ligand of Adgrg6 (adhesion G protein–coupled receptor G6; also known as Gpr126) on Schwann cells to promote myelin homeostasis. As the name suggests, ubiquitin—and ubiquitination—is found in all eukaryotic cells and has been implicated in the regulation of nearly all cellular processes. Ubiquitination involves a three-enzyme cascade, in which ubiquitin is activated by the E1 enzyme, in a process that requires ATP; activated ubiquitin is transferred to the E2 ubiquitin–conjugating enzyme and finally covalently linked to the substrate by the E3 ubiquitin ligase. [Panel (A) is reprinted with permission from Like GPCRs, protein kinases are implicated in various disease states and are therefore promising targets for therapy. Samelson, The ability of Sos1 to oligomerize the adaptor protein LAT is separable from its guanine nucleotide exchange activity in vivo. Excess activity of glycogen synthase kinase 3 (GSK-3) may contribute to various neurological disorders, including Alzheimer’s disease. Two nominations concerned the application of insights into G protein–coupled receptor (GPCR) signaling to disorders involving the nervous system, Dohlman drew our attention to a study that used a computational approach to build a better opioid (Fig. Although the use of opioids to relieve pain dates back thousands of years, their pain-relieving properties are counterbalanced by serious side effects, such as addiction and potentially fatal respiratory depression, and their abuse has become a serious global problem () used the recently reported crystal structure of the μ-opioid receptor to computationally dock more than 3 million compounds to the ligand-binding pocket, in the hopes of identifying compounds that engaged the receptor in new ways to stabilize unique conformations. The authors then used structure-based optimization to synthesize PZM21, a compound that displayed Gα-biased signaling and, remarkably, potently elicited long-lasting relief from pain in mice.