bims-pideca 2026-04-26 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–04–26
six papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Cell shapes decode molecular phenotypes in image-based spatial proteomics.
Cancer signaling beyond the genes.
Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass.
Repurposing drugs for treating the neurobehavioral manifestations of PTEN hamartoma tumor syndrome.
Comprehensive profiling of clinically approved kinase inhibitors reveals mutation-specific inhibitors and opportunities for drug repurposing.
Ubiquitination of glycogen and metabolites in cells and tissues.

Cell Syst. 2026 Apr 20. pii: S2405-4712(26)00071-2. [Epub ahead of print] 101589

Cell shapes decode molecular phenotypes in image-based spatial proteomics.

Trang Le, William D Leineweber, Matheus P Viana, Anthony Cesnik, Jan N Hansen, Wei Ouyang, Susanne M Rafelski, Emma Lundberg.

  Cellular and tissue structures arise from a few cell shapes, which undergo transformations based on biophysical constraints. Despite links between signaling pathways and cellular geometry, whole-proteome orchestration in association with cell shape is underexplored. In this study, over 1 million single cells stained for 11,998 proteins across 11 cell lines in the Human Protein Atlas were analyzed for organelle, pathway, and single-protein levels in association with cellular shapespace. We found that cell and nuclear shapes across cell lines exist in a shared continuum. The subcellular organelle topology varies across cell lines but remains consistent within each cell line's shapespace. At the single-protein level, cells of different shapes in the same cell-cycle phase might be preparing for different fates, and many non-cell-cycle proteins expressed shape-based abundance variation. Using a shape-based coordinate framework, we analyzed the distribution shift of protein spatial localization under drug perturbation.

Keywords:  cell shape; interpretable machine learning; molecular variation; morphological variation; single cell; spatial proteomics

DOI:  https://doi.org/10.1016/j.cels.2026.101589
Curr Opin Cell Biol. 2026 Apr 17. pii: S0955-0674(26)00031-1. [Epub ahead of print]100 102643

Cancer signaling beyond the genes.

Andre Levchenko, Ralitsa R Madsen.

Cancer is still largely interpreted through the lens of genetic mutations, which continues to shape most therapeutic strategies. Yet single cell analyses reveal limits to this view: phenotypic heterogeneity is pervasive even among genetically identical cancer cells, and many canonical driver mutations are also present in non-malignant tissues. These paradoxes can be reconciled by viewing cancer as a new tissue state characterized by aberrant cellular information processing, where mutations act as context-dependent modifiers of the signaling codes. We advance a framework in which input-specific signaling dynamics determine phenotypic outcomes, while oncogenic mutations bias and blur these dynamics rather than acting as simple "on-off" switches. In this view, therapeutic success depends on restoring the fidelity of dynamic signal encoding and decoding rather than merely inhibiting isolated pathway components.

DOI: https://doi.org/10.1016/j.ceb.2026.102643
Biochem J. 2026 May 06. 483(5): 761-775

Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass.

Dhirendra K Simanshu, Frank McCormick.

  Distinct effector-binding preferences among RAS family GTPases challenge the longstanding view that canonical RAS proteins uniformly bind and activate RAF, PI3Kα, RalGDS, and other downstream effectors. Quantitative binding data, supported by structural insights into effector recognition, instead reveal a division of labor: the canonical RAS subfamily (KRAS, HRAS, NRAS) binds RAF kinases with high affinity, the RRAS subfamily (RRAS2 and MRAS) preferentially engages PI3Kα, and the RAP subfamily (RAP1A and RAP1B) shows the strongest binding to RalGDS. These intrinsic preferences, encoded in the switch regions and further shaped by isoform and effector expression, as well as subcellular localization, establish a hierarchy in which canonical RAS, RRAS2/MRAS, and RAP1A/B primarily activate RAF, PI3Kα, and RalGDS, respectively, in normal cells. Oncogenic mutations at codons G12, G13, or Q61 disrupt this hierarchy by driving sustained accumulation of GTP-bound canonical RAS, enabling engagement of lower-affinity effectors such as PI3Kα and RalGDS. In addition, certain mutations, including KRAS-G12D and -G12V, modestly enhance PI3Kα binding, representing a neomorphic expansion of effector engagement. Together, these effects bypass intrinsic effector selectivity, allowing canonical RAS to co-opt effectors normally associated with other RAS subfamilies and broaden downstream signaling. This framework explains how inherent effector preferences govern normal signaling and how oncogenic mutations override these constraints to expand effector engagement in RAS-driven cancers.

Keywords:  KRAS; RAF1; RAS; RRAS2; Rap1; phosphoinositide 3-kinase

DOI:  https://doi.org/10.1042/BCJ20250142
iScience. 2026 Apr 17. 29(4): 115428

Repurposing drugs for treating the neurobehavioral manifestations of PTEN hamartoma tumor syndrome.

Tim Fieblinger, Judith Rudolph, Kerstin Müller, Petra Friess, Nicole Weigelt, Christina Thiede, Simone Modolo, Denise Federico, Malik Majandinow, Federico Tinarelli, Vivian J A Costantini, Pier P Marrese, Annalisa Mercuri, Nikisha Carty, Ana Christina Gomes, Maria A Whitehead, Philip A Gerrard, Chrisovalantis Papadopoulos, Paul Elvin.

  PTEN hamartoma tumor syndrome (PHTS) is caused by mutation of PTEN and patients suffer from an increased risk of cancer and neurodevelopmental disorders. While treatment with mTOR inhibitors can alleviate some aspects, there remains a significant need for treatment of neurobehavioral symptoms in PHTS. Here, we describe a drug-repurposing program, screening >60 compounds targeting the PI3K/AKT/mTOR pathway. First, we interrogated altered signaling and morphology in a cell-line and primary neurons with PTEN-dysfunction, before further refining our compound selection using multielectrode recordings and MDCK assays. A final number of six compounds, with promising potency and propensity to cross the blood-brain-barrier, were tested in vivo in pharmacokinetic and proof-of-principle pharmacodynamic studies, and we observed that dual PI3K/mTOR inhibitors achieve effects comparable to or even surpassing those of standard mTOR inhibitors. In summary, our study showcases a combination of in vitro models providing a valid strategy for identifying drug-repurposing candidates to treat PHTS patients.

Keywords:  Cancer systems biology; Molecular biology; Pharmaceutical science

DOI:  https://doi.org/10.1016/j.isci.2026.115428
Nat Biotechnol. 2026 Apr 20.

Comprehensive profiling of clinically approved kinase inhibitors reveals mutation-specific inhibitors and opportunities for drug repurposing.

Mehlam Saifudeen, Songli Zhu, Shuguang Liang, Mia Eason, Alison Goupil, Deanna F Mische, Christian M Loch, Haiching Ma, Marina Chan, Taranjit S Gujral.

Protein kinases are central to cell signaling and key drug targets in cancer. To inform potential repurposing of kinase inhibitors, we profiled 86 of the ~100 approved kinase inhibitors against 758 kinases, including 409 wild-type and 349 oncogenic variants using a biochemical kinase assay. Our results increase the number of druggable kinases from 89 to 235, revealing that 94% of mutations and 97% of fusions represented in our samples are inhibited by at least one existing drug. The dataset revealed mutation-specific selectivity, especially in tyrosine kinases FGFR and MET, highlighting gaps and repurposing opportunities. We experimentally validated several actionable findings, including tepotinib to target the IRAK1/4-cholesterol pathway in glioblastoma, brigatinib to target the MARK2/3-Hippo pathway in pancreatic cancer and gilteritinib to overcome MET mutation-driven drug resistance and metastasis. To facilitate exploration of our data, we provide KIRHub, a web-based tool that allows identification of existing inhibitors of wild-type and mutated kinases to guide precision oncology.

DOI: https://doi.org/10.1038/s41587-026-03090-8
Nature. 2026 Apr 22.

Ubiquitination of glycogen and metabolites in cells and tissues.

Marco Jochem, Simon A Cobbold, Craig A Goodman, Catharina Kueng, Anthony Cerra, Laura F Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S Wang, Simon R Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M Devine, Martin Brzozowski, Yuri Shibata, Niall D Geoghegan, Catriona A McLean, Bernhard C Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander.

Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.

DOI: https://doi.org/10.1038/s41586-026-10548-x