bims-pimaco 2022-08-28 papers

J Chem Inf Model. 2022 Aug 24.

Structural and Dynamic Effects of PTEN C-Terminal Tail Phosphorylation.

Iris N Smith, Jennifer E Dawson, James Krieger, Stetson Thacker, Ivet Bahar, Charis Eng.

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene encodes a tightly regulated dual-specificity phosphatase that serves as the master regulator of PI3K/AKT/mTOR signaling. The carboxy-terminal tail (CTT) is key to regulation and harbors multiple phosphorylation sites (Ser/Thr residues 380-385). CTT phosphorylation suppresses the phosphatase activity by inducing a stable, closed conformation. However, little is known about the mechanisms of phosphorylation-induced CTT-deactivation dynamics. Using explicit solvent microsecond molecular dynamics simulations, we show that CTT phosphorylation leads to a partially collapsed conformation, which alters the secondary structure of PTEN and induces long-range conformational rearrangements that encompass the active site. The active site rearrangements prevent localization of PTEN to the membrane, precluding lipid phosphatase activity. Notably, we have identified phosphorylation-induced allosteric coupling between the interdomain region and a hydrophobic site neighboring the active site in the phosphatase domain. Collectively, the results provide a mechanistic understanding of CTT phosphorylation dynamics and reveal potential druggable allosteric sites in a previously believed clinically undruggable protein.

DOI: https://doi.org/10.1021/acs.jcim.2c00441

Cell Cycle. 2022 Aug 25. 1-37

Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation.

Pierluigi Scalia, Stephen J Williams, Yoko Fujita-Yamaguchi, Antonio Giordano.

In proliferating cells and tissues a number of checkpoints (G1/S and G2/M) preceding cell division (M-phase) require the signal provided by growth factors present in serum. IGFs (I and II) have been demonstrated to constitute key intrinsic components of the peptidic active fraction of mammalian serum. In vivo genetic ablation studies have shown that the cellular signal triggered by the IGFs through their cellular receptors represents a non-replaceable requirement for cell growth and cell cycle progression. Retroactive and current evaluation of published literature sheds light on the intracellular circuitry activated by these factors providing us with a better picture of the pleiotropic mechanistic actions by which IGFs regulate both cell size and mitogenesis under developmental growth as well as in malignant proliferation. The present work aims to summarize the cumulative knowledge learned from the IGF ligands/receptors and their intracellular signaling transducers towards control of cell size and cell-cycle with particular focus to their actionable circuits in human cancer. Furthermore, we bring novel perspectives on key functional discriminants of the IGF growth-mitogenic pathway allowing re-evaluation on some of its signal components based upon established evidences.

Keywords: (scavenger protein for IGF2 & mannose-6-phosphate); GF; GH; HybR; HybR-A; IGF-I/II: insulin like growth factor peptides; IGF-Type I receptor gene; IGF1R; IGF1R/IR hybrid receptor; IGF1R/IR-A; IR (also InsR); IR isoform A (exon 11-); IR-A; IRS; Insulin-like growth factor receptor; RTK; growth factor; growth hormone; igf1/2; igf1r; igf2r/m6pr/SpI2-6; insr; insulin like growth factor genes; insulin receptor gene; insulin receptor protein; insulin receptor substrate; mTOR; mTOR complex. additional acronyms are clarified in the text; mTORC; mammalian target of rapamycin; property of a GF to increase growth (hypertrophy) and number (hyperplasia) of a target cell or tissue; receptor tyrosine kinase; trans-membrane high affinity IGF2 scavenger protein; trophic (effect); type I (protein)

DOI: https://doi.org/10.1080/15384101.2022.2108117

J Am Chem Soc. 2022 Aug 24.

Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.

Ziyang Zhang, Johannes Morstein, Andrew K Ecker, Keelan Z Guiley, Kevan M Shokat.

KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other KRAS hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.

DOI: https://doi.org/10.1021/jacs.2c05377

Nat Rev Clin Oncol. 2022 Aug 26.

The current state of the art and future trends in RAS-targeted cancer therapies.

Salman R Punekar, Vamsidhar Velcheti, Benjamin G Neel, Kwok-Kin Wong.

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

DOI: https://doi.org/10.1038/s41571-022-00671-9

Nucleic Acids Res. 2022 Aug 22. pii: gkac704. [Epub ahead of print]

Distinct, opposing functions for CFIm59 and CFIm68 in mRNA alternative polyadenylation of Pten and in the PI3K/Akt signalling cascade.

Hsin-Wei Tseng, Anthony Mota-Sydor, Rania Leventis, Predrag Jovanovic, Ivan Topisirovic, Thomas F Duchaine.

Precise maintenance of PTEN dosage is crucial for tumor suppression across a wide variety of cancers. Post-transcriptional regulation of Pten heavily relies on regulatory elements encoded by its 3'UTR. We previously reported the important diversity of 3'UTR isoforms of Pten mRNAs produced through alternative polyadenylation (APA). Here, we reveal the direct regulation of Pten APA by the mammalian cleavage factor I (CFIm) complex, which in turn contributes to PTEN protein dosage. CFIm consists of the UGUA-binding CFIm25 and APA regulatory subunits CFIm59 or CFIm68. Deep sequencing analyses of perturbed (KO and KD) cell lines uncovered the differential regulation of Pten APA by CFIm59 and CFIm68 and further revealed that their divergent functions have widespread impact for APA in transcriptomes. Differentially regulated genes include numerous factors within the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway that PTEN counter-regulates. We further reveal a stratification of APA dysregulation among a subset of PTEN-driven cancers, with recurrent alterations among PI3K/Akt pathway genes regulated by CFIm. Our results refine the transcriptome selectivity of the CFIm complex in APA regulation, and the breadth of its impact in PTEN-driven cancers.

DOI: https://doi.org/10.1093/nar/gkac704