bims-pimaco 2024-06-02 papers

Issue of 2024–06–02
five papers selected by
Lucas B. Zeiger

J Biol Chem. 2024 May 28. pii: S0021-9258(24)01924-0. [Epub ahead of print] 107423

Molecular determinants of Ras-mTORC2 signaling.

Stephen F Smith, A F M Tariqul Islam, Shoxruxxon Alimukhamedov, Ethan T Weiss, Pascale G Charest.

Recent research has identified the mechanistic Target of Rapamycin Complex 2 (mTORC2) as a conserved direct effector of Ras proteins. While previous studies suggested the involvement of the Switch I (SWI) effector domain of Ras in binding mTORC2 components, the regulation of the Ras-mTORC2 pathway is not entirely understood. In Dictyostelium, mTORC2 is selectively activated by the Ras protein RasC, and the RasC-mTORC2 pathway then mediates chemotaxis to cAMP and cellular aggregation by regulating the actin cytoskeleton and promoting cAMP signal relay. Here, we investigated the role of specific residues in RasC's SWI, C-terminal allosteric domain, and hypervariable region (HVR) related to mTORC2 activation. Interestingly, our results suggest that RasC SWI residue A31, which was previously implicated in RasC-mediated aggregation, regulates RasC's specific activation by the Aimless RasGEF. On the other hand, our investigation identified a crucial role for RasC SWI residue T36, with secondary contributions from E38 and allosteric domain residues. Finally, we found that conserved basic residues and the adjacent prenylation site in the HVR, which are crucial for RasC's membrane localization, are essential for RasC-mTORC2 pathway activation by allowing for both RasC's own cAMP-induced activation and its subsequent activation of mTORC2. Therefore, our findings revealed new determinants of RasC-mTORC2 pathway specificity in Dictyostelium, contributing to a deeper understanding of Ras signaling regulation in eukaryotic cells.

Keywords: Dictyostelium; HVR; RasC; allosteric domain; hypervariable region; mTOR; mechanistic Target of Rapamycin Complex 2; switch I

DOI: https://doi.org/10.1016/j.jbc.2024.107423

Acta Pharm Sin B. 2024 May;14(5): 1895-1923

Targeting RAF dimers in RAS mutant tumors: From biology to clinic.

Huanhuan Yin, Qiulin Tang, Hongwei Xia, Feng Bi.

RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

Keywords: Cancer therapy; Drug resistance; RAF dimerization; RAF inhibitors; RAS mutations

DOI: https://doi.org/10.1016/j.apsb.2024.02.018

Cell Signal. 2024 May 23. pii: S0898-6568(24)00202-X. [Epub ahead of print]120 111234

Collagen XVII promotes dormancy of colorectal cancer cells by activating mTORC2 signaling.

Jinlong Lin, Bingxu Zou, Hongbo Li, Jing Wang, Shuman Li, Jinghua Cao, Dan Xie, Fengwei Wang.

Tumor dormancy is the underpinning for cancer relapse and chemoresistance, leading to massive cancer-related death in colorectal cancer (CRC). However, our comprehension of the mechanisms dictating tumor dormancy and strategies for eliminating dormant tumor cells remains restricted. In this study, we identified that collagen XVII (COL17A1), a hemidesmosomal transmembrane protein, can promote the dormancy of CRC cells. The upregulation of COL17A1 was observed to prolong quiescence periods and diminish drug susceptibility of CRC cells. Mechanistically, COL17A1 acts as a scaffold, enhancing the crosstalk between mTORC2 and Akt, thereby instigating the mTORC2-mediated dormant signaling. Notably, the activation of mTORC2 is contingent upon the intracellular domain of COL17A1, regardless of its ectodomain shedding. Our findings underscore a pivotal role of the COL17A1-mTORC2 axis in CRC dormancy, suggesting that mTORC2-specific inhibitors may hold therapeutic prospects for the eradication of dormant tumor cells.

Keywords: COL17A1; CRC; Dormancy; Scaffold; mTORC2

DOI: https://doi.org/10.1016/j.cellsig.2024.111234

Cell Death Dis. 2024 May 29. 15(5): 373

Combined inhibition of class 1-PI3K-alpha and delta isoforms causes senolysis by inducing p21WAF1/CIP1 proteasomal degradation in senescent cells.

Judith Neuwahl, Chantal A Neumann, Annika C Fitz, Anica D Biermann, Maja Magel, Annabelle Friedrich, Lorenz Sellin, Björn Stork, Roland P Piekorz, Peter Proksch, Wilfried Budach, Reiner U Jänicke, Dennis Sohn.

The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.

DOI: https://doi.org/10.1038/s41419-024-06755-x

Nat Commun. 2024 May 31. 15(1): 4666

A theory of evolutionary dynamics on any complex population structure reveals stem cell niche architecture as a spatial suppressor of selection.

Yang Ping Kuo, César Nombela-Arrieta, Oana Carja.

How the spatial arrangement of a population shapes its evolutionary dynamics has been of long-standing interest in population genetics. Most previous studies assume a small number of demes or symmetrical structures that, most often, act as well-mixed populations. Other studies use network theory to study more heterogeneous spatial structures, however they usually assume small, regular networks, or strong constraints on the strength of selection considered. Here we build network generation algorithms, conduct evolutionary simulations and derive general analytic approximations for probabilities of fixation in populations with complex spatial structure. We build a unifying evolutionary theory across network families and derive the relevant selective parameter, which is a combination of network statistics, predictive of evolutionary dynamics. We also illustrate how to link this theory with novel datasets of spatial organization and use recent imaging data to build the cellular spatial networks of the stem cell niches of the bone marrow. Across a wide variety of parameters, we find these networks to be strong suppressors of selection, delaying mutation accumulation in this tissue. We also find that decreases in stem cell population size also decrease the suppression strength of the tissue spatial structure.

DOI: https://doi.org/10.1038/s41467-024-48617-2