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Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activationmore » « less
Abstract Beyond the most common oncogenes activated by mutation (mut-drivers), there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and posttranslational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function. The list of putative mut-drivers includes established drivers and others with poorly understood roles in cancer. This ML model is available as a web application. As a case study, we focused the approach on nonreceptor tyrosine kinases (NRTK) and found a recurrent mutation in activated CDC42 kinase-1 (ACK1) that disrupts the Mig6 homology region (MHR) and ubiquitin-association (UBA) domains on the ACK1 C-terminus. By studying these domains in cultured cells, we found that disruption of the MHR domain helps activate the kinase while disruption of the UBA increases kinase stability by blocking its lysosomal degradation. This ACK1 mutation is analogous to lymphoma-associated mutations in its sister kinase, TNK1, which also disrupt a C-terminal inhibitory motif and UBA domain. This study establishes a mut-driver discovery tool for the research community and identifies a mechanism of ACK1 hyperactivation shared among ACK family kinases.
Implications: This research identifies a potentially targetable activating mutation in ACK1 and other possible oncogenic mutations, including PTM-disrupting mutations, for further study.
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This study explores the tensile behavior and dynamical heterogeneity of sodium montmorillonite under extreme conditions using molecular dynamics simulations, providing insights to advance the development of clay minerals for engineering applications.
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Abstract The Lyme disease spirochete
Borrelia burgdorferi causes an infection with diverse clinical outcomes, which can include arthritis as well as cardiac and neurological manifestations.B. burgdorferi expresses different outer surface lipoproteins at different stages in its infectious cycle, many of which are adhesins. Utilizing atomic force microscopy (AFM), we obtained topography images and force–distance curves of wild-typeB. burgdorferi and mutant strains encoding different complements of surface lipoproteins. AFM data show that a reduced number of genome-encoded lipoproteins correlates with decreased binding probability, weakens unbinding force, and negatively affects cell elasticity.Free, publicly-accessible full text available December 14, 2024
