bims-pimaco 2021-07-25 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2021–07–25
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

SAR1B senses leucine levels to regulate mTORC1 signalling.
AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild-type KRAS and BRAF by destabilizing Aurora kinase B.
The mTOR-Autophagy Axis and the Control of Metabolism.
Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.
How the amino acid leucine activates the key cell-growth regulator mTOR.
Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
The TOR-dependent phosphoproteome and regulation of cellular protein synthesis.

Nature. 2021 Jul 21.

SAR1B senses leucine levels to regulate mTORC1 signalling.

Jie Chen, Yuhui Ou, Rong Luo, Jie Wang, Dong Wang, Jialiang Guan, Yi Li, Peixue Xia, Peng R Chen, Ying Liu.

The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B-GATOR2-mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.

DOI: https://doi.org/10.1038/s41586-021-03768-w
Cancer Discov. 2021 Jul 23. pii: candisc.0815.2020. [Epub ahead of print]

AKT degradation selectively inhibits the growth of PI3K/PTEN pathway mutant cancers with wild-type KRAS and BRAF by destabilizing Aurora kinase B.

Jia Xu, Xufen Yu, Tiphaine C Martin, Ankita Bansal, Kakit Cheung, Abigail Lubin, Elias Stratikopoulos, Kaitlyn M Cahuzac, Li Wang, Ling Xie, Royce Zhou, Yudao Shen, Xuewei Wu, Shen Yao, Ruifang Qiao, Poulikos I Poulikakos, Xian Chen, Jing Liu, Jian Jin, Ramon Parsons.

Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K/PTEN pathway lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation but not kinase inhibition profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2/M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader resistant lines were associated with low AKT phosphorylation, wild type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K/PTEN pathway mutation without RAS pathway mutation, suggesting that these cancer patients could benefit from AKT degrader therapy that leads to loss of AURKB.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0815
Front Cell Dev Biol. 2021 ;9 655731

The mTOR-Autophagy Axis and the Control of Metabolism.

Nerea Deleyto-Seldas, Alejo Efeyan.

  The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.

Keywords:  autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients

DOI:  https://doi.org/10.3389/fcell.2021.655731
Cancer Sci. 2021 Jul 20.

Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.

Sakura Hiraide, Masanobu Takahashi, Yuya Yoshida, Hideharu Yamada, Keigo Komine, Chikashi Ishioka.

  Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and EGFR inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of the BRAF inhibitor dabrafenib (DAB) and the MEK inhibitor trametinib (TRA), we screened 240 miRNA in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the anti-proliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.

Keywords:  BRAF; Colorectal cancer; MAPK signaling; Mcl1; miR-193a-3p

DOI:  https://doi.org/10.1111/cas.15075
Nature. 2021 Jul 21.

How the amino acid leucine activates the key cell-growth regulator mTOR.

Tibor Vellai.



Keywords:  Cancer; Cell biology; Metabolism

DOI:  https://doi.org/10.1038/d41586-021-01943-7
Cell. 2021 Jul 14. pii: S0092-8674(21)00796-0. [Epub ahead of print]

Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.

Charles L Evavold, Iva Hafner-Bratkovič, Pascal Devant, Jasmin M D'Andrea, Elsy M Ngwa, Elvira Boršić, John G Doench, Martin W LaFleur, Arlene H Sharpe, Jay R Thiagarajah, Jonathan C Kagan.

  The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).

Keywords:  gasdermin D; inflammasomes; inflammation; innate immunity; macrophages; mtorc1; pyroptosis; ragulator; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cell.2021.06.028
EMBO J. 2021 Jul 23. e107911

The TOR-dependent phosphoproteome and regulation of cellular protein synthesis.

Tiffany Mak, Andrew W Jones, Paul Nurse.

  Cell growth is orchestrated by a number of interlinking cellular processes. Components of the TOR pathway have been proposed as potential regulators of cell growth, but little is known about their immediate effects on protein synthesis in response to TOR-dependent growth inhibition. Here, we present a resource providing an in-depth characterisation of Schizosaccharomyces pombe phosphoproteome in relation to changes observed in global cellular protein synthesis upon TOR inhibition. We find that after TOR inhibition, the rate of protein synthesis is rapidly reduced and that notable phosphorylation changes are observed in proteins involved in a range of cellular processes. We show that this reduction in protein synthesis rates upon TOR inhibition is not dependent on S6K activity, but is partially dependent on the S. pombe homologue of eIF4G, Tif471. Our study demonstrates the impact of TOR-dependent phospho-regulation on the rate of protein synthesis and establishes a foundational resource for further investigation of additional TOR-regulated targets both in fission yeast and other eukaryotes.

Keywords:  TOR regulation; phosphoproteomics; protein synthesis

DOI:  https://doi.org/10.15252/embj.2021107911