The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4DCAF1. Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

Highlights d Kibra WW tandem domains bind to Dendrin with lownanomolar affinity d Structure of Kibra WW domains bound to Dendrin PY motifs reveals the binding mechanism d Disruption of the Kibra/Dendrin interaction impairs learning and memory in mice d A Kibra mutation associated with Tourette syndrome causes defects in Dendrin binding

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.

WW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite sequence specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins including β-Dystroglycan, JCAD, and PTPN21. The WW tandem-mediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.

Background The systemic immune‐inflammation index (SII) is correlated with patient survival in various types of solid tumors. However, only a few studies have focused on the prognostic value of the SII in patients with surgically resected non‐small cell lung cancer (NSCLC). Methods This study was a single center retrospective analysis of 569 NSCLC patients who underwent curative lobectomy at the Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between 2006 and 2012. A receiver operating characteristic curve was plotted to compare the discriminatory ability of the SII for overall survival (OS). A Cox proportional hazards regression model was used to perform univariate and multivariate analyses. Results The SII, neutrophil‐lymphocyte ratio (NLR), and platelet‐lymphocyte ratio (PLR) all correlated with OS in NSCLC patients, and the SII was an independent prognostic factor for OS (hazard ratio 1.256, 95% confidence interval 1.018–1.551; P = 0.034). The area under the receiver operating characteristic curve of the SII (0.547) was larger than the NLR (0.541) and PLR (0.531). Furthermore, the SII retained prognostic significance in the lung adenocarcinoma subgroup. Conclusion The SII is a promising prognostic predictor for patients with surgically resected NSCLC and retained prognostic significance in the lung adenocarcinoma subgroup. The prognostic value of the SII is superior to the NLR and PLR.

The human absent in melanoma 2 (AIM2) is considered as a DNA recognizer. AIM2 has been described as a tumor suppressor gene in the early years. But recent studies suggested that it functions as an oncogene in several cancers. However, its roles in non-small-cell lung cancer (NSCLC) remain unclear. Here we reported that AIM2 highly expressed in NSCLC cells and exhibited a tumor-promoting property both in vitro and in vivo. Besides, AIM2 short hairpin RNA (shRNA)-mediated suppression of cell proliferation was triggered by the accumulation of cells at the G2/M phase.Knockdown of AIM2 reduced the inflammasome formation, while overexpression of AIM2 or stimulation by poly(dA:dT) induced the inflammasome formation. Interestingly, blockade of the inflammasome by caspase-1 inhibitor VX-765 or ASC small interfering RNA (siRNA) abolished the effects brought by AIM2 shRNA and AIM2 plasmid. In summary, our results revealed that AIM2 functioned as an oncogene in NSCLC in an inflammasome-dependent way.

Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3–5R. Double N-methylated compound 18 showed a pKi of 8.73 ± 0.08 (Ki = 1.92 ± 0.34 nM) and a pEC50 of 9.13 ± 0.04 (EC50 = 0.75 ± 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery.

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