α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure.

Epithelial cells can become polyploid upon tissue injury, but mechanosensitive cues that trigger this state are poorly understood. Using an Madin Darby Canine Kidney (MDCK) cell knock-out/reconstitution system, we show that α-catenin mutants that alter force-sensitive binding to F-actin or middle (M)-domain promote cytokinesis failure and binucleation, particularly near epithelial wound-fronts. We identified Leucine Zipper Tumor Suppressor 2 (LZTS2), a factor previously implicated in abscission, as a conformation sensitive proximity partner of α-catenin.

α-catenin phosphorylation is elevated during mitosis to resist apical rounding and epithelial barrier leak.

Epithelial cell cohesion and barrier function critically depend on α-catenin, an actin-binding protein and essential constituent of cadherin-catenin-based adherens junctions. α-catenin undergoes actomyosin force-dependent unfolding of both actin-binding and middle domains to strongly engage actin filaments and its various effectors; this mechanosensitivity is critical for adherens junction function. We previously showed that α-catenin is highly phosphorylated in an unstructured region that links the mechanosensitive middle and actin-binding domains (known as the P-linker region), but the cellular processes that promote α-catenin phosphorylation have remained elusive.

5-HT Receptors in the BNST Modulate Contextual Fear Conditioning Without Affecting Acute Early Life Stress-Enhanced Fear Learning in Adult Rats.

Background/objectives: Rodents provide a useful translational model of fear- and anxiety-related behaviors. Previously stressed animals exhibit physiological and behavioral stress responses that parallel those observed in anxious humans. Patients diagnosed with post-traumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms that result from exposure to one or more traumatic events, with individuals exposed to early adverse experiences and women having increased vulnerability for diagnoses; however, the mechanisms of this increased vulnerability remain unknown.

IL6 and IL6R as Prognostic Biomarkers in Colorectal Cancer.

Colorectal cancer is the third most diagnosed malignancy worldwide and survival outcomes remain poor. Research is focused on the identification of novel prognostic and predictive biomarkers to improve clinical practice. There is robust evidence in the literature that inflammatory cytokine interleukin-6 (IL6) is elevated systemically in CRC patients and that this phenomenon is a predictor of poor survival outcome.

Combining Fundamental Kinetics and Standard Alkylation Assays to Prioritize Lead-Like KRAS G12C Inhibitors.

We measure the fundamental rate constants of internally discovered KRAS G12C inhibitors to demonstrate how kinetic analyses can be integrated with standard biochemical and cell-based assays for more optimal biophysical compound prioritization. In this proof-of-principle study, we characterize three irreversible covalent inhibitors targeting the mutant cysteine at the switch II binding pocket. We estimate the three fundamental kinetic rate constants ( , , ) that define the contributions of affinity and inactivation to the overall alkylation rate for a more complete biophysical characterization.