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1. MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression

   https://doi.org/10.7554/eLife.60541  

   Aikin, Timothy J; Peterson, Amy F; Pokrass, Michael J; Clark, Helen R; Regot, Sergi (September 2020, eLife)

   null (Ed.)

   In animals, the MAPK pathway is a network of genes that helps a cell to detect and then respond to an external signal by switching on or off a specific genetic program. In particular, cells use this pathway to communicate with each other. In an individual cell, the MAPK pathway shows fluctuations in activity over time. Mutations in the genes belonging to the MAPK pathway are often one of the first events that lead to the emergence of cancers. However, different mutations in the genes of the pathway can have diverse effects on a cell’s behavior: some mutations cause the cell to divide while others make it migrate. Recent research has suggested that these effects may be caused by changes in the pattern of MAPK signaling activity over time. Here, Aikin et al. used fluorescent markers to document how different MAPK mutations influence the behavior of a human breast cell and its healthy neighbors. The experiments showed that cells with different MAPK mutations behaved in one of two ways: the signaling quickly pulsed between high and low levels of activity, or it remained at a sustained high level. In turn, these two signaling patterns altered cell behavior in different ways. Pulsed signaling led to more cell division, while sustained signaling stopped division and increased migration. Aikin et al. then examined the effect of the MAPK mutations on neighboring healthy cells. Sustained signaling from the cancerous cell caused a wave of signaling activity in the surrounding cells. This led the healthy cells to divide and migrate toward the cancerous cell, pushing it out of the tissue layer. It is not clear if these changes protect against or promote cancer progression in living tissue. However, these results explain why specific cancer mutations cause different behaviors in cells. 

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2. Pseudophosphatase MK-STYX: the atypical member of the MAP kinase phosphatases

   Hinton, Shantá D. (May 2020, FEBS journal)

   The regulation of the phosphorylation of mitogen activated protein kinases (MAPKs) is essential for cellular processes such as proliferation, differentiation, survival and death. Mutations within the MAPK signaling cascades are implicated in diseases such as cancer, neurodegenerative disorders, arthritis, obesity and diabetes. MAPK phosphorylation is controlled by an intricate balance between MAPK kinases (enzymes that add phosphate groups) and MAPK phosphatases (MKPs) (enzymes that remove phosphate groups). MKPs are complex negative regulators of the MAPK pathway that control the amplitude and spatiotemporal regulation of MAPKs. MK-STYX (MAPK phosphoserine/threonine/tyrosine-binding protein) is a member of the MKP subfamily, which lacks the critical histidine and nucleophilic cysteine residues in the active site required for catalysis. MK-STYX does not influence the phosphorylation status of MAPK, but even so it adds to the complexity of signal transduction cascades as a signaling regulator. This review highlights the function of MK-STYX, providing insight into MK-STYX as a signal regulating molecule in the stress response, HDAC 6 dynamics, apoptosis, and neurite differentiation. 

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3. The non-canonical Wnt receptor Ror2 is required for cartilage cell polarity and morphogenesis of the craniofacial skeleton in zebrafish

   https://doi.org/10.1242/dev.201273  

   Dranow, Daniel B.; Le Pabic, Pierre; Schilling, Thomas F. (April 2023, Development)

   ABSTRACT Non-canonical/β-catenin-independent Wnt signaling plays crucial roles in tissue/cell polarity in epithelia, but its functions have been less well studied in mesenchymal tissues, such as the skeleton. Mutations in non-canonical Wnt signaling pathway genes cause human skeletal diseases such as Robinow syndrome and Brachydactyly Type B1, which disrupt bone growth throughout the endochondral skeleton. Ror2 is one of several non-canonical Wnt receptor/co-receptors. Here, we show that ror2−/− mutant zebrafish have craniofacial skeletal defects, including disruptions of chondrocyte polarity. ror1−/− mutants appear to be phenotypically wild type, but loss of both ror1 and ror2 leads to more severe cartilage defects, indicating partial redundancy. Skeletal defects in ror1/2 double mutants resemble those of wnt5b−/− mutants, suggesting that Wnt5b is the primary Ror ligand in zebrafish. Surprisingly, the proline-rich domain of Ror2, but not its kinase domain, is required to rescue its function in mosaic transgenic experiments in ror2−/− mutants. These results suggest that endochondral bone defects in ROR-related human syndromes reflect defects in cartilage polarity and morphogenesis. 

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4. Genetic mutation and biological pathway prediction based on whole slide images in breast carcinoma using deep learning

   https://doi.org/10.1038/s41698-021-00225-9  

   Qu, Hui; Zhou, Mu; Yan, Zhennan; Wang, He; Rustgi, Vinod K.; Zhang, Shaoting; Gevaert, Olivier; Metaxas, Dimitris N. (September 2021, npj Precision Oncology)

   Abstract Breast carcinoma is the most common cancer among women worldwide that consists of a heterogeneous group of subtype diseases. The whole-slide images (WSIs) can capture the cell-level heterogeneity, and are routinely used for cancer diagnosis by pathologists. However, key driver genetic mutations related to targeted therapies are identified by genomic analysis like high-throughput molecular profiling. In this study, we develop a deep-learning model to predict the genetic mutations and biological pathway activities directly from WSIs. Our study offers unique insights into WSI visual interactions between mutation and its related pathway, enabling a head-to-head comparison to reinforce our major findings. Using the histopathology images from the Genomic Data Commons Database, our model can predict the point mutations of six important genes (AUC 0.68–0.85) and copy number alteration of another six genes (AUC 0.69–0.79). Additionally, the trained models can predict the activities of three out of ten canonical pathways (AUC 0.65–0.79). Next, we visualized the weight maps of tumor tiles in WSI to understand the decision-making process of deep-learning models via a self-attention mechanism. We further validated our models on liver and lung cancers that are related to metastatic breast cancer. Our results provide insights into the association between pathological image features, molecular outcomes, and targeted therapies for breast cancer patients. 

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5. Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics

   https://doi.org/10.1073/pnas.2006764117  

   Tucholski, Trisha; Cai, Wenxuan; Gregorich, Zachery R.; Bayne, Elizabeth F.; Mitchell, Stanford D.; McIlwain, Sean J.; de Lange, Willem J.; Wrobbel, Max; Karp, Hannah; Hite, Zachary; et al (October 2020, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. Although the genetic cause of HCM has been linked to mutations in genes encoding sarcomeric proteins, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited. Moreover, how mutations in different sarcomeric proteins can result in highly similar clinical phenotypes remains unknown. Posttranslational modifications (PTMs) and alternative splicing regulate the function of sarcomeric proteins; hence, it is critical to study HCM at the level of proteoforms to gain insights into the mechanisms underlying HCM. Herein, we employed high-resolution mass spectrometry–based top-down proteomics to comprehensively characterize sarcomeric proteoforms in septal myectomy tissues from HCM patients exhibiting severe outflow track obstruction ( n = 16) compared to nonfailing donor hearts ( n = 16). We observed a complex landscape of sarcomeric proteoforms arising from combinatorial PTMs, alternative splicing, and genetic variation in HCM. A coordinated decrease of phosphorylation in important myofilament and Z-disk proteins with a linear correlation suggests PTM cross-talk in the sarcomere and dysregulation of protein kinase A pathways in HCM. Strikingly, we discovered that the sarcomeric proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably consistent, regardless of the underlying HCM-causing mutations. This study suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct genotype, which underscores the importance of molecular characterization of HCM phenotype and presents an opportunity to identify broad-spectrum treatments to mitigate the most severe manifestations of this genetically heterogenous disease. 

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