Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by ) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified . A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules.

Exploring the conformational landscape of protein kinases.

Protein kinases are dynamic enzymes that display complex regulatory mechanisms. Although they possess a structurally conserved catalytic domain, significant conformational dynamics are evident both within a single kinase and across different kinases in the kinome. Here, we highlight methods for exploring this conformational space and its dynamics using kinase domains from ABL1 (Abelson kinase), PKA (protein kinase A), AurA (Aurora A), and PYK2 (proline-rich tyrosine kinase 2) as examples.

Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression.

Despite progress in treating or preventing viral hepatitis, a leading cause of liver cancer, hepatocellular cancer (HCC) continues to be a major cause of cancer-related deaths globally. HCC is a highly heterogeneous cancer with many genetic alterations common within a patient's tumor and between different patients. This complicates therapeutic strategies.

Using quantitative immunohistochemistry in patients at high risk for hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer death worldwide. Early detection is key to effective treatment. Yet, early diagnosis is challenging, especially in patients with cirrhosis, who are at high risk of developing HCC.

Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver.

Dysregulated transforming growth factor-beta (TGF-β) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-β signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-β signaling-deficient mice (SPTBN1 ) and the mutant mice had reduced SIRT6 abundance in the liver.

TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer.

Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination.

Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling.

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC).

Secretome profiling identifies neuron-derived neurotrophic factor as a tumor-suppressive factor in lung cancer.

Clinical and preclinical studies show tissue-specific differences in tumorigenesis. Tissue specificity is controlled by differential gene expression. We prioritized genes that encode secreted proteins according to their preferential expression in normal lungs to identify candidates associated with lung cancer.

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4).

Focus Issue: Cancer-Beyond tumor genetics to protein landscapes.

The proteins that regulate cell proliferation, metastatic potential, survival in circulation, and immune evasion represent most of the targets for therapeutic intervention in cancer. Furthermore, genomic profiling of just the cancer cells leaves critical information about the tumor microenvironment in the dark. The articles highlighted in this Focus Issue describe efforts to translate genomic data into knowledge of aberrant signaling that can be therapeutically targeted and strategies to explore not only the changes that occur in the protein landscape of the tumors but also in the protein profiles of the tumor microenvironment.

Pseudophosphatase as E3 ubiquitin ligase inhibitor.

The pseudophosphatase STYX prevents the substrate recognition subunit FBXW7 from binding the catalytic E3 ubiquitin ligase complex.

Daily oxygen rhythms.

The hypoxia response system and circadian clock system are interconnected.

Lysosomes get into the action.

Activity-dependent lysosomal fusion with the plasma membrane stimulates dendrite remodeling.

Translational complex for differentiation.

NAT1 interacts with a subset of eukaryotic translation initiation factors to enable expression of transcripts required for stem cell differentiation signals.

New connections: NHERF gates activity.

The NHERF molecular adaptors serve as gates for TRPC4 and TRPC5 regulation by diacylglycerol and recognition of CFTR by the quality control checkpoint.

Tumors block pain with CXCL12.

The chemokine CXCL12 released from early stage pancreatic cancer recruits Schwann cells and suppresses pain signaling.

Emerging roles for organelles in cellular regulation.

This Editorial Guide describes the emerging confluence of cellular regulation and organelle biology. The signals and molecular machineries that regulate organelle function, dynamics, and replication and the signals produced by organelles are beginning to be discovered.

Unveiling the molecular details of plant signaling.

This Editorial Guide describes emerging areas of signaling research for plants. Advances in this area are key to preserving nature and maintaining the planet's health while feeding a growing human population.

Signaling proteins in the spotlight.

The molecular side of signaling still has many secrets to reveal. This Editorial Guide describes areas of particular interest with regard to understanding cellular regulation at the level of individual molecules and macromolecular complexes. Advances in technology and the accumulation of proteomic and genomic data reveal previously unknown components of signaling networks, the spatial organization of macromolecular complexes, and how information flows through the networks to produce specific cellular responses.

Focus Issue: New insights in GPCR to G protein signaling.

This Focus Issue highlights new discoveries at the level of the receptor, the α subunit, and the βγ subunit and spans research in yeast on polarized growth and G protein-coupled receptor (GPCR) trafficking, in mice on an orphan GPCR with constitutive activity, and a disease-causing mutation in an α subunit that results in inappropriate GPCR-G protein coupling.

Beyond canonical: The Wnt and β-catenin story.

This Editorial Guide uses Wnt-stimulated activation of the transcriptional activity of β-catenin, the canonical Wnt/β-catenin pathway, to illustrate the hazards of limiting research investigation and questions to those that fit the "canonical" view.

Leveraging signaling research to understand and treat disease.

This Editorial Guide describes an area of active signaling research. A challenge signaling researchers face is understanding how the information gained by analysis at the cellular and molecular levels can be translated to understanding higher-order organismal physiology and pathophysiology.