Article
Multidisciplinary Sciences
Lick Pui Lai, Nicole Fer, William Burgan, Vanessa E. Wall, Bingfang Xu, Daniel Soppet, Dominic Esposito, Dwight Nissley, Frank McCormick
Summary: RAF inhibitors unexpectedly activate ERK signaling in both normal and tumor cells with elevated RAS activity. This study demonstrates that RAF inhibitors can cause paradoxical ERK activation in KRAS(G12C)-dependent lung cancer cell lines. It also reveals that classical RAS proteins are not essential for this process, and the MRAS/SHOC2 complex plays a vital role.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Daniel A. Bonsor, Dhirendra K. Simanshu
Summary: RAF activation is a crucial step for signal transduction in the MAPK pathway. The SHOC2-MRAS-PP1C (SMP) holoenzyme complex, consisting of SHOC2, MRAS, and PP1C, plays a key role in activating RAF kinases. Recent research has provided valuable insights into the structure and function of the SMP complex, including its assembly, the impact of the nucleotide state of MRAS, and the involvement of SHOC2 and MRAS in PP1C activity and specificity. Understanding the SMP complex could lead to potential therapeutic strategies for RAS/RAF-driven cancers and RASopathies.
Review
Cell Biology
Reiko Sugiura, Ryosuke Satoh, Teruaki Takasaki
Summary: The RAF/MEK/ERK signaling pathway regulates various cellular processes and its activation is linked to cell proliferation and cancer. Further research on the mechanisms of ERK activation is essential for developing effective cancer treatments.
Review
Biochemistry & Molecular Biology
Jason J. Kwon, William C. Hahn
Summary: SHOC2 is a key scaffold protein that plays a critical role in RTK/RAS signaling, facilitating downstream receptor tyrosine kinase (RTK) and RAS signaling while mediating various cellular and developmental processes.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Zachary J. Hauseman, Michelle Fodor, Anxhela Dhembi, Jessica Viscomi, David Egli, Melusine Bleu, Stephanie Katz, Eunyoung Park, Dong Man Jang, Kathryn A. Porter, Fabian Meili, Hongqiu Guo, Grainne Kerr, Sandra Molle, Camilo Velez-Vega, Kim S. Beyer, Giorgio G. Galli, Saveur-Michel Maira, Travis Stams, Kirk Clark, Michael J. Eck, Luca Tordella, Claudio R. Thoma, Daniel A. King
Summary: This study provides a structural understanding of the MRAS-SHOC2-PP1C complex and reveals its role in the RAS-driven and multi-molecular model for RAF activation, shedding light on mechanisms of clinically observed enhanced RAS-MAPK signaling and providing a structural basis for therapeutic interventions.
Review
Biochemistry & Molecular Biology
Yanlin Song, Zhenfei Bi, Yu Liu, Furong Qin, Yuquan Wei, Xiawei Wei
Summary: Molecular target inhibitors have been approved for tumor treatment and mainly target cell proliferation and metabolism. The RAS-RAF-MEK-ERK pathway plays essential roles in cell functions and abnormal activation of this pathway leads to tumor development. In this review, the development and potential combinations of inhibitors targeting this pathway are discussed.
Article
Multidisciplinary Sciences
Jason J. Kwon, Behnoush Hajian, Yuemin Bian, Lucy C. Young, Alvaro J. Amor, James R. Fuller, Cara V. Fraley, Abbey M. Sykes, Jonathan So, Joshua Pan, Laura Baker, Sun Joo Lee, Douglas B. Wheeler, David L. Mayhew, Nicole S. Persky, Xiaoping Yang, David E. Root, Anthony M. Barsotti, Andrew W. Stamford, Charles K. Perry, Alex Burgin, Frank McCormick, Christopher T. Lemke, William C. Hahn, Andrew J. Aguirre
Summary: This study uses cryo-electron microscopy to determine the structure of the SHOC2-MRAS-PP1C complex and investigate the functional consequences of SHOC2 missense variants. The research reveals the mechanism of complex formation and the enhanced activity of mutant versions. This study is of great importance for understanding cellular signal transduction and the pathogenesis of RAS-related diseases.
Review
Pharmacology & Pharmacy
Yunli Huang, Yongqi Zhen, Yanmei Chen, Shaoguang Sui, Lan Zhang
Summary: This article provides a comprehensive review of the interplay between the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their application in cancer therapy. The impact of small molecule inhibitors targeting this pathway on autophagy is discussed, and the advantages and limitations of combining these inhibitors with autophagy inhibitors are explored.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Fisheries
Linlin Zhang, Lu Chen, Meng Qi, Fuchang Yu, Xiaotong Ni, Haozheng Hong, Haotian Xu, Shiwen Xu
Summary: Glyphosate exposure induces autophagy in hepatic L8824 cells by activating nitric oxide (NO), regulating energy metabolism, and activating the RAS/RAF/MEK/ERK signaling pathway. This study provides insight into the mechanism of glyphosate toxicity and its effects on cellular processes.
FISH & SHELLFISH IMMUNOLOGY
(2023)
Article
Oncology
Weifeng Wan, Wenfeng Xiao, Wen Pan, Ligang Chen, Zhiyong Liu, Jianguo Xu
Summary: This study demonstrates that the upregulation of ICMT expression is associated with glioblastoma, and its pharmacological inhibitors effectively suppress glioblastoma growth and act synergistically with chemotherapy drugs. Therefore, ICMT represents a promising target for the treatment of glioblastoma.
CANCER CHEMOTHERAPY AND PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Morgan R. Packer, Jillian A. Parker, Jean K. Chung, Zhenlu Li, Young Kwang Lee, Trinity Cookis, Hugo Guterres, Steven Alvarez, Md Amin Hossain, Daniel P. Donnelly, Jeffrey N. Agar, Lee Makowski, Matthias Buck, Jay T. Groves, Carla Mattos
Summary: Studies demonstrate that Raf-Ras binding domain (Raf-RBD) can induce Ras dimerization at low surface densities and in solution, with robust connections between two Raf-RBD D113 residues confirmed by molecular dynamics simulations. These results suggest that Raf-RBD binding and Ras dimerization occur together, forming a high-affinity signaling complex.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Microbiology
Bao-Rui Zhao, Xin-Xin Wang, Xian-Wei Wang
Summary: This study found that MjShoc2 in kuruma shrimp interacts with Vibrio anguillarum flagellin A (FlaA) and mediates its induced expression. The study established the Flagellin/MjShoc2/Erk/Stat signaling axis and revealed a new antibacterial strategy in shrimp.
Article
Oncology
Wenwen Geng, Meiling Cao, Ke Dong, Junhua An, Haidong Gao
Summary: Our study revealed that aberrant activation of the mTOR pathway is a characteristic alteration in triple-negative breast cancer (TNBC), but the mTOR pathway inhibitor everolimus is not effective for TNBC patients. We identified that the activation of the ERK pathway is an important mechanism of resistance to everolimus in TNBC cells, and SHOC2 plays a critical role in mediating this pathway. Knockdown of SHOC2 significantly inhibited the activation of the Raf-ERK pathway induced by everolimus. Moreover, interference with SHOC2 expression in combination with everolimus had significant effects on cell cycle progression and apoptosis in vitro experiments.
CANCER BIOLOGY & THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Trinity Cookis, Carla Mattos
Summary: The interaction between Ras and Raf-kinase through the Raf's Ras-binding and CRD domains is crucial for signal transduction. The Ras dimer model formed through the alpha 4-alpha 5 interface plays a key role in regulating the function of Ras and Raf.
Article
Oncology
Ying Zhang, Qian Lu, Nan Li, Ming Xu, Tatsuo Miyamoto, Jing Liu
Summary: Sulforaphane (SFN), a natural compound derived from broccoli, has been found to significantly inhibit migration and invasion of breast cancer cells by affecting cytoskeleton formation. SFN can also directly bind to RAF family proteins and inhibit phosphorylation of the signaling pathway. These findings suggest that SFN has the potential to be used as a therapeutic drug to inhibit breast cancer cell metastasis.
Article
Multidisciplinary Sciences
Lucy C. Young, Nicole Hartig, Isabel Boned del Rio, Sibel Sari, Benjamin Ringham-Terry, Joshua R. Wainwright, Greg G. Jones, Frank McCormick, Pablo Rodriguez-Viciana
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Multidisciplinary Sciences
Greg G. Jones, Isabel Boned del Rio, Sibel Sari, Aysen Sekerim, Lucy C. Young, Nicole Hartig, Itziar Areso Zubiaur, Mona A. El-Bahrawy, Rob E. Hynds, Winnie Lei, Miriam Molina-Arcas, Julian Downward, Pablo Rodriguez-Viciana
NATURE COMMUNICATIONS
(2019)
Article
Multidisciplinary Sciences
Timothy H. Tran, Albert H. Chan, Lucy C. Young, Lakshman Bindu, Chris Neale, Simon Messing, Srisathiyanarayanan Dharmaiah, Troy Taylor, John-Paul Denson, Dominic Esposito, Dwight V. Nissley, Andrew G. Stephen, Frank McCormick, Dhirendra K. Simanshu
Summary: This study presents molecular details of the RAS-RAF interaction, including the crystal structures of KRAS binding with RAF1 and a proposed model of membrane-bound RAS-RAF complex formation.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Anne E. Roehrig, Kristina Klupsch, Juan A. Oses-Prieto, Selim Chaib, Stephen Henderson, Warren Emmett, Lucy C. Young, Silvia Surinova, Andreas Blees, Anett Pfeiffer, Maha Tijani, Fabian Brunk, Nicole Hartig, Marta Munoz-Alegre, Alexander Hergovich, Barbara H. Jennings, Alma L. Burlingame, Pablo Rodriguez-Viciana
Summary: The study investigates the roles of the PAF complex and Merlin tumor suppressor protein in RNA processing, highlighting their interaction for growth suppression. Additionally, the involvement of FAT cadherins in regulating Merlin-PAFC interaction is identified as a significant finding from the research.
Article
Multidisciplinary Sciences
Rowan Howell, James Davies, Matthew A. Clarke, Anna Appios, Yashoda Jayal, Ben Ringham-Terry, Isabel Boned Del Rio, Jasmin Fisher, Clare L. Bennett
Summary: Researchers have developed an in silico model to investigate the interaction between melanomas and Langerhans cells (LCs). The model suggests that melanomas do not activate LC migration to lymph nodes until they reach a critical size, due to a positive TNF-alpha feedback loop. Experimental testing confirms that treating primary tumors with MAPK pathway inhibitors can prevent LC migration. The study also predicts treatment combinations that can bypass LC dysfunction.
Meeting Abstract
Oncology
Isabel Boned del Rio, Lucy C. Young, Sibel Sari, Greg G. Jones, Amandeep Bhamra, Silvia Surinova, Pablo Rodriguez-Viciana
MOLECULAR CANCER RESEARCH
(2020)
Meeting Abstract
Oncology
Greg G. Jones, Isabel Boned Del Rio, Sibel Sari, Aysen Sekerim, Lucy C. Young, Nicole Hartig, Mona A. El-Bahrawy, Miriam Molina-Arcas, Julian Downward, Pablo Rodriguez-Viciana
MOLECULAR CANCER RESEARCH
(2020)
Meeting Abstract
Oncology
Sibel Sari, Isabel Boned del Rio, Greg Jones, Jake Henry, Maria De Las Nieves Amalia Peltzer, York Posor, Sergio Quezada, Pablo Rodriguez-Viciana
MOLECULAR CANCER RESEARCH
(2020)