Article
Multidisciplinary Sciences
Yann Ehinger, Ziyang Zhang, Khanhky Phamluong, Drishti Soneja, Kevan M. Shokat, Dorit Ron
Summary: Alcohol Use Disorder (AUD) is a common issue with limited treatment options. Research suggests mTORC1 as a potential therapeutic target, but chronic use may lead to severe side effects. The study proposes a binary drug strategy, utilizing a combination of drugs to protect mTORC1 activity in the periphery and mitigate adverse effects.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Toshihiko Oki, Francois Mercier, Hiroki Kato, Yookyung Jung, Thomas O. McDonald, Joel A. Spencer, Michael C. Mazzola, Nick van Gastel, Charles P. Lin, Franziska Michor, Toshio Kitamura, David T. Scadden
Summary: This study investigates the real-time dynamics of the mTORC1 pathway in relation to AML growth and response to chemotherapy using fluorescent markers, showing a decrease and subsequent increase in mTORC1 activity with AML progression and maximal chemotherapy response, respectively. Data also suggests that chemotherapy induces mTORC1 activity, and timed inhibition of mTORC1 enhances killing of AML cells. These findings provide insights for targeted intervention strategies in AML treatment.
NATURE COMMUNICATIONS
(2021)
Article
Biochemical Research Methods
Cemal Erdem, Adrian V. Lee, D. Lansing Taylor, Timothy R. Lezon
Summary: Insulin and insulin-like growth factor I (IGF1) receptors play a crucial role in the risk and advancement of various cancer types by activating cell survival cascades. A dual receptor computational model identified the role of ribosomal protein S6 kinase in regulating MAPK and Akt activation levels in response to Ins and IGF1 stimulation. The study suggests potential new targets for anti-IGF1R cancer therapy.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Cell Biology
Jiayang Cai, Zhang Ye, Yuanyuan Hu, Liguo Ye, Lun Gao, Yixuan Wang, Qian Sun, Shiao Tong, Shenqi Zhang, Liquan Wu, Ji'an Yang, Qianxue Chen
Summary: In this study, we found that fatostatin induces ferroptosis in glioblastoma by inhibiting the AKT/mTORC1/GPX4 signaling pathway. Fatostatin also inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. Additionally, we developed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which can penetrate the blood-brain barrier and target GBM.
CELL DEATH & DISEASE
(2023)
Article
Biology
Rigao Chen, Fei Yang, Yong Wang, Xinling Wang, Xiaohong Fan
Summary: This study revealed a novel mechanism by which mTORC1 signaling controls the survival of nucleus pulposus cells, offering potential strategies for clinical intervention in lumbar disc herniation. By inhibiting mTORC1 activity, nucleus pulposus cell survival can be promoted, showing the importance of metabolic homeostasis in IVD degeneration.
BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Mingyuan Chen, Tengqian Sun, Yanghao Zhong, Xin Zhou, Jin Zhang
Summary: This study investigates Akt activity and regulation on lysosomes, showing that 3-phosphoinositides accumulate on lysosomal surface and play a crucial role in Akt and mTORC1 activation.
ACS CENTRAL SCIENCE
(2021)
Article
Oncology
Niamh Coleman, Vivek Subbiah, Shubham Pant, Keyur Patel, Sinchita Roy-Chowdhuri, Sireesha Yedururi, Amber Johnson, Timothy A. Yap, Jordi Rodon, Kenna Shaw, Funda Meric-Bernstam
Summary: Understanding mechanisms of acquired resistance to molecular targeted therapy is crucial for improving patient outcomes and developing effective treatment strategies. The case presented highlights the rare occurrence of mTOR mutations as a mechanism of resistance and the importance of tumor molecular profiling in precision medicine.
NPJ PRECISION ONCOLOGY
(2021)
Article
Cell Biology
Katharina Joechle, Huda Jumaa, Kerstin Thriene, Claus Hellerbrand, Birte Kulemann, Stefan Fichtner-Feigl, Sven A. Lang, Jessica Guenzle
Summary: The study showed that OSI-027, a dual kinase inhibitor targeting mTOR complexes, can significantly impact the migratory and metastatic capacity of cholangiocarcinoma cells by reducing cell mobility and migration, decreasing colony-forming ability, and downregulating MMP2 and MMP9 expression. Additionally, OSI-027 impaired survival and anti-apoptotic signaling as determined by AKT and MAPK blotting, suggesting that dual targeting of mTORC1/2 may be a viable option for anti-neoplastic therapy in CCA.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Gianluca Figlia, Sandra Mueller, Anna M. Hagenston, Susanne Kleber, Mykola Roiuk, Jan-Philipp Quast, Nora ten Bosch, Damian Carvajal Ibanez, Daniela Mauceri, Ana Martin-Villalba, Aurelio A. Teleman
Summary: The research shows that different Rag GTPase genes and isoforms can differentially regulate mTORC1 activity and modulate the responsiveness of mammalian cells to amino acid availability. This sheds light on the important role of the mechanistic target of rapamycin complex 1 (mTORC1) in regulating cellular anabolism and catabolism.
NATURE CELL BIOLOGY
(2022)
Article
Cell Biology
Meher Bolisetti Gayatri, Navya Naidu Gajula, Suresh Chava, Aramati B. M. Reddy
Summary: This study demonstrates the role of glutamine in modulating the fate of MSCs through the crosstalk between mTOR complexes and identifies a critical switch in signaling. Furthermore, it highlights the importance of glutamine in modulating molecular cues involved in diabetes-induced bone adipogenesis and other secondary complications.
CELL DEATH DISCOVERY
(2022)
Article
Multidisciplinary Sciences
Alicia Hernandez-Vivanco, Nuria Cano-Adamuz, Alberto Sanchez-Aguilera, Alba Gonzalez-Alonso, Alberto Rodriguez-Fernandez, Inigo Azcoitia, Liset Menendez de la Prida, Pablo Mendez
Summary: Using a combination of molecular, genetic, functional and behavioural tools, this study describes the impact of brain synthesized estrogen on inhibitory neuronal function, network oscillations and hippocampal dependent memory.
NATURE COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Joseph L. Damstra-Oddy, Eleanor C. Warren, Christopher J. Perry, Yann Desfougeres, John-Mark K. Fitzpatrick, Judith Schaf, Lisa Costelloe, William Hind, Eric J. Downer, Adolfo Saiardi, Robin S. B. Williams
Summary: The study found that both CBD and CBG regulate mTORC1 signaling through a mechanism dependent on the activity of the upstream IPMK signaling pathway. This has potential relevance for the treatment of mTOR-related disorders, including multiple sclerosis.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Jordan S. Farrell, Matthew Lovett-Barron, Peter M. Klein, Fraser T. Sparks, Tilo Gschwind, Anna L. Ortiz, Biafra Ahanonu, Susanna Bradbury, Satoshi Terada, Mikko Oijala, Ernie Hwaun, Barna Dudok, Gergely Szabo, Mark J. Schnitzer, Karl Deisseroth, Attila Losoncz, Ivan Soltesz
Summary: Research has identified neurons in the supramammillary nucleus (SuM) that are highly correlated with future locomotor speed and reliably drive locomotion. Specifically, Tac1-expressing neurons in the SuM were found to control the activity of speed-modulated hippocampal neurons. These findings suggest that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a way that may support spatial navigation.
Article
Biochemistry & Molecular Biology
Belen Sanz-Castillo, Begona Hurtado, Diana Vara-Ciruelos, Aicha El Bakkali, Dario Hermida, Beatriz Salvador-Barbero, Diego Martinez-Alonso, Jose Gonzalez-Martinez, Clara Santiveri, Ramon Campos-Olivas, Pilar Ximenez-Embun, Javier Munoz, Monica Alvarez-Fernandez, Marcos Malumbres
Summary: This study reveals that the cell cycle kinase MASTL/Greatwall inhibits the activity of the PI3K-AKT signaling pathway by phosphorylating the PP2A/B55 inhibitor ENSA/ARPP19, thus limiting AKT activity. Furthermore, the study finds that MASTL is directly phosphorylated by mTORC1, which limits the dephosphorylation of IRS1 and GRB10 downstream of mTORC1, further restraining AKT activity. This research highlights the importance of the MASTL-PP2A/B55 kinase-phosphatase module in controlling AKT and maintaining metabolic homeostasis.
Review
Biochemistry & Molecular Biology
Seo Hyeong Park, Won Hoon Choi, Min Jae Lee
Summary: mTOR, a mechanistic target, plays a crucial role in regulating cellular homeostasis and cell growth, including autophagy and proteasome activity. Inhibition of mTORC1 can induce autophagy, while proteasomes provide amino acids necessary for protein synthesis. Understanding the connection between mTORC1 activity and proteasome function is important for the evaluation of mTORC1 inhibitors as therapeutic treatments.
Article
Medicine, General & Internal
Deborah Wingard, JoAnn Trejo, Monica Gudea, Seneca Goodman, Vivian Reznik
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
(2019)
Review
Cell Biology
Michael R. Dores, JoAnn Trejo
Article
Biochemistry & Molecular Biology
Neil J. Grimsey, Ying Lin, Rachan Narala, Cara C. Rada, Hilda Mejia-Pena, JoAnn Trejo
JOURNAL OF BIOLOGICAL CHEMISTRY
(2019)
Article
Biochemistry & Molecular Biology
Stacy D. Ochoa, Michael R. Dores, John M. Allen, Tuan Tran, Maryan Osman, Nidia P. Vazquez Castellanos, JoAnn Trejo, Ricardo M. Zayas
BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION
(2019)
Article
Multidisciplinary Sciences
Ying Lin, Jacob M. Wozniak, Neil J. Grimsey, Sravan Girada, Anand Patwardhan, Olivia Molinar-Inglis, Thomas H. Smith, John D. Lapek, David J. Gonzalez, Joann Trejo
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
Article
Biology
Jeremiah Keyes, Ambhighainath Ganesan, Olivia Molinar-Inglis, Archer Hamidzadeh, Jinfan Zhang, Megan Ling, JoAnn Trejo, Andre Levchenko, Jin Zhang
Article
Multidisciplinary Sciences
Dequina A. Nicholas, Vashti S. Knight, Karen J. Tonsfeldt, Tomohiro Terasaka, Olivia Molinar-Inglis, Shannon B. Z. Stephens, JoAnn Trejo, Alexander S. Kauffman, Pamela L. Mellon, Mark A. Lawson
SCIENTIFIC REPORTS
(2020)
Article
Cell Biology
JoAnn Trejo
MOLECULAR BIOLOGY OF THE CELL
(2020)
Review
Pharmacology & Pharmacy
Anand Patwardhan, Norton Cheng, JoAnn Trejo
Summary: G protein-coupled receptors (GPCRs) are a large family of signaling receptors that regulate cellular and physiologic responses, implicated in various diseases. Although phosphorylation is a major regulator of GPCR signaling, other post-translational modifications (PTMs) such as ubiquitination, glycosylation, and palmitoylation play important roles in GPCR biology, yet understanding of these PTMs is limited. Comprehensive understanding of diverse PTMs is crucial for elucidating dysregulated mechanisms in disease and improving drug development for GPCRs.
PHARMACOLOGICAL REVIEWS
(2021)
Article
Biochemistry & Molecular Biology
An-Angela N. Van, Maya T. Kunkel, Timothy R. Baffi, Gema Lorden, Corina E. Antal, Sourav Banerjee, Alexandra C. Newton
Summary: Gene fusions involving protein kinase C (PKC) are unique and distinct from oncogenic fusions, presenting a mechanism for loss of PKC function in cancer. PKC catalytic domain fusions are functionally lost due to instability, while PKC regulatory domain fusions compete for diacylglycerol to suppress endogenous PKC activity.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Ryan Weeks, Xin Zhou, Tina L. Yuan, Jin Zhang
Summary: In this study, a ratiometric Ras activity reporter (RasAR) was developed to quantitatively measure Ras activity in living cells with high spatiotemporal resolution. By utilizing RasAR, researchers successfully explored the activities of different Ras isoforms, revealed the role of Src kinase as an upstream regulator to inhibit HRas, and investigated the effects of KRasG12C inhibitors on Ras activity in living cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Medicine, Research & Experimental
Joseph M. Valentine, Maryam Ahmadian, Omer Keinan, Mohammad Abu-Odeh, Peng Zhao, Xin Zhou, Mark P. Keller, Hui Gao, Ruth T. Yu, Christopher Liddle, Michael Downes, Jin Zhang, Aldons J. Lusis, Alan D. Attie, Ronald M. Evans, Mikael Ryden, Alan R. Saltier
Summary: This study investigates the resistance of multiple hormones in obesity and reveals that catecholamine resistance and elevated inflammation lead to the downregulation of beta 3-adrenergic receptor expression. The study also demonstrates that the induction of the pseudokinase TRIB1, downstream of the EPAC/RAP2A/PI-PLC pathway, triggers both homologous and heterologous desensitization of the Adrb3 receptor, inhibiting lipolysis and energy expenditure.
JOURNAL OF CLINICAL INVESTIGATION
(2022)