Article
Cell Biology
Sachin Surve, Simon C. Watkins, Alexander Sorkin
Summary: The study demonstrated that endogenous KRAS and NRAS are predominantly localized to the plasma membrane and do not colocalize with endosomal EGFR upon EGF stimulation. It was suggested that a small pool of surface EGFRs sustain signaling within the RAS-ERK1/2 pathway.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Oren Yakovian, Julia Sajman, Michal Alon, Rand Arafeh, Yardena Samuels, Eilon Sherman
Summary: NRas is a crucial mediator of the mitogenic pathway in both normal and cancer cells, and its signaling is regulated by dynamic interactions with functional clusters of BRAF or other related proteins at the plasma membrane.
Article
Biology
Ian M. Ahearn, Helen R. Court, Farid Siddiqui, Daniel Abankwa, Mark R. Philips
Summary: ICMT is crucial for the efficient delivery of NRAS to the plasma membrane, as well as for its carboxyl methylation, binding with PDE6d, and flux through the Golgi.
LIFE SCIENCE ALLIANCE
(2021)
Article
Biochemical Research Methods
Sachio Suzuki, Masaru Yoshikawa, Shunsuke Sawada, Neal K. Devaraj, Shinya Tsukiji
Summary: Conjugating small-molecule ligands to synthetic motifs that can localize to specific organelles or membranes is a practical approach to manipulate biological processes. We have developed a synthetic myristoyl-DCys motif that can undergo S-palmitoylation and localize to the Golgi surface. By miniaturizing the myristoyl-DCys motif, we have identified four new derivatives that retain the palmitoylation-dependent Golgi localization property. These miniaturized motifs can be used to generate small-molecule ligand conjugates for protein localization and cell signaling control.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Dhirendra K. Simanshu, Mark R. Philips, John F. Hancock
Summary: One open question in RAS biology is the existence and role of RAS dimers in RAF dimerization and activation. The hypothesis of RAS dimers arose from the discovery of RAF kinases functioning as obligate dimers, suggesting that G-domain-mediated RAS dimerization might nucleate RAF dimer formation. This review presents evidence on RAS dimerization and discusses a recent consensus among RAS researchers that the clustering of multiple RAS proteins is not due to the stable association of G-domains, but rather to the membrane phospholipids and RAS C-terminal membrane anchors.
Article
Oncology
Luying Li, Peipei Ding, Xinyue Lv, Suhong Xie, Ling Li, Jianfeng Chen, Danlei Zhou, Xiaochao Wang, Qi Wang, Wei Zhang, Yanqing Xu, Renquan Lu, Weiguo Hu
Summary: T-cell-mediated immunotherapy is a promising cancer treatment strategy, but a deeper understanding of the T-cell immune response is needed. This study demonstrates that intracellular CD59 regulates the subcellular compartmentalization of Ras, affecting T-cell activation, proliferation, and function.
CANCER IMMUNOLOGY RESEARCH
(2022)
Review
Chemistry, Physical
Thomas R. Shaw, Subhadip Ghosh, Sarah L. Veatch
Summary: Lateral organization in the plasma membrane plays a crucial role in biological processes. Recent experimental support suggests that lipid organization is important in modulating membrane heterogeneity. The concept of liquid-liquid phase separation explains the observed heterogeneity and predicts responses to membrane composition perturbations.
ANNUAL REVIEW OF PHYSICAL CHEMISTRY, VOL 72
(2021)
Article
Biochemistry & Molecular Biology
Yuankai Chang, Mianmian Shi, Yanfeng Sun, Hui Cheng, Xiaobin Ou, Yi Zhao, Xuebin Zhang, Brad Day, Chen Miao, Kun Jiang
Summary: The opening and closing of plant stomata is regulated by light-responsive proteins and metabolic activities. A metabolite called 12-oxo-phytodienoic acid (OPDA) negatively regulates stomatal response to light, preventing excessive water loss. OPDA affects the activities of proton pumps and potassium channels, ultimately impacting plant growth and water use efficiency.
Article
Biochemistry & Molecular Biology
Francisco S. Mesquita, Laurence Abrami, Arthur Samurkas, F. Gisou van Der Goot
Summary: S-acylation is a covalent modification of proteins with fatty acids, allowing dynamic control of protein properties and functions in association with cell membranes. It regulates a substantial portion of the human proteome and has increasingly recognized roles in protein lifespan. Recent advancements have provided new insights into its mechanisms and implications. This review focuses on the importance of S-acylation in the homeostasis, function, and coordination of integral membrane proteins.
Article
Cell Biology
Shuangshuang Wang, Hua Qian, Liwei Zhang, Panpan Liu, Dexuan Zhuang, Qun Zhang, Fuxiang Bai, Zhihong Wang, Yonggan Yan, Jing Guo, Jun Huang, Xunwei Wu
Summary: Mutant H-Ras(G12V) induces autophagy in human keratinocytes, which is strongly regulated by the calcineurin/NFAT pathway. Activation of NFATc1 by H-Ras(G12V) promotes its nuclear translocation, suggesting a role in H-Ras-induced autophagy. Inhibition of the calcineurin/NFAT pathway suppresses H-Ras expression and potentially disrupts the binding of NFATc1 to the H-Ras promoter region.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Editorial Material
Biochemistry & Molecular Biology
John F. Hancock, Alemayehu A. Gorfe
Summary: Activation of the RAF-MEK-MAPK cascade is the critical event in KRAS signaling and oncogenic transformation, which involves assembly of a multiprotein-lipid complex on the plasma membrane. Mysore et al. have now provided the first glimpse of what this structure may actually look like.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ruth Nussinov, Chung-Jung Tsai, Hyunbum Jang
Summary: High-resolution technologies have clarified some principles underlying cellular actions, but understanding how cells receive, communicate, and respond to signals remains challenging. Cells navigate long-range diffusion-controlled signaling via association/dissociation of spatially proximal entities.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Review
Cell Biology
Muhammad U. Anwar, F. Gisou van der Goot
Summary: S-acylation is an important posttranslational modification that regulates cellular processes. This reversible lipid modification affects cellular pathways and physiological processes, and the enzymes and proteins involved in S-acylation are still being discovered and studied.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Cell Biology
Radoslaw J. Gora, Babette de Jong, Patrick van Hage, Mary Ann Rhiemus, Fjodor van Steenis, John van Noort, Thomas Schmidt, Marcel J. M. Schaaf
Summary: In this study, single-molecule microscopy was used to investigate the dynamics of H-Ras protein in zebrafish embryos. The results showed the presence of fast- and slow-diffusing subpopulations of molecules within the plasma membrane, which are influenced by the structure and composition of the membrane. Additionally, differences between cells within the same embryo were found to contribute to the variability in the data. These findings highlight the importance of single-molecule microscopy for studying factors influencing protein dynamics in an intact living organism.
DISEASE MODELS & MECHANISMS
(2022)
Article
Multidisciplinary Sciences
Helgi I. Ingolfsson, Chris Neale, Timothy S. Carpenter, Rebika Shrestha, Cesar A. Lopez, Timothy H. Tran, Tomas Oppelstrup, Harsh Bhatia, Liam G. Stanton, Xiaohua Zhang, Shiv Sundram, Francesco Di Natale, Animesh Agarwal, Gautham Dharuman, Sara I. L. Kokkila Schumacher, Thomas Turbyville, Gulcin Gulten, Que N. Van, Debanjan Goswami, Frantz Jean-Francois, Constance Agamasu, De Chen, Jeevapani J. Hettige, Timothy Travers, Sumantra Sarkar, Michael P. Surh, Yue Yang, Adam Moody, Shusen Liu, Brian C. Van Essen, Arthur F. Voter, Arvind Ramanathan, Nicolas W. Hengartner, Dhirendra K. Simanshu, Andrew G. Stephen, Peer-Timo Bremer, S. Gnanakaran, James N. Glosli, Felice C. Lightstone, Frank McCormick, Dwight Nissley, Frederick H. Streitz
Summary: In this study, a scale-bridging ensemble of over 100,000 simulations of RAS-membrane interactions was created using machine learning. The simulations revealed distinctive patterns of lipid composition that are correlated with RAS dynamics, potentially providing a mechanism for regulating cell signaling cascades.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Hitesh Patel, Jun Li, Ana Herrero, Jakob Kroboth, Adam Byron, Alex Von Kriegsheim, Valerie Brunton, Neil Carragher, Toby Hurd, Margaret Frame
SCIENTIFIC REPORTS
(2020)
Article
Cell Biology
Paula Colon-Bolea, Rocio Garcia-Gomez, Sue Shackleton, Piero Crespo, Xose R. Bustelo, Berta Casar
MOLECULAR BIOLOGY OF THE CELL
(2020)
Article
Oncology
Yaiza Garcia-Ibanez, Garcilaso Riesco-Eizaguirre, Pilar Santisteban, Berta Casar, Piero Crespo
Editorial Material
Biochemistry & Molecular Biology
Kylie J. Walters, Piero Crespo
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Miguel Angel Merlos Rodrigo, Hana Michalkova, Vladislav Strmiska, Berta Casar, Piero Crespo, Vivian de los Rios, J. Ignacio Casal, Yazan Haddad, Roman Guran, Tomas Eckschlager, Petra Pokorna, Zbynek Heger, Vojtech Adam
Summary: This study revealed that up-regulation of metallothionein-3 (hMT3) in neuroblastoma cells was associated with increased cisplatin resistance, indicating a potential cause for tumor relapse. Multiple biological pathways related to apoptosis, transport, proteasome, and cellular stress were implicated in cisplatin resistance in hMT3-overexpressing neuroblastoma cells.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Thaidy Moreno, Beatriz Monterde, Laura Gonzalez-Silva, Isabel Betancor-Fernandez, Carlos Revilla, Antonio Agraz-Doblas, Javier Freire, Pablo Isidro, Laura Quevedo, Rosa Blanco, Santiago Montes-Moreno, Laura Cereceda, Aurora Astudillo, Berta Casar, Piero Crespo, Cristina Morales Torres, Paola Scaffidi, Javier Gomez-Roman, Eduardo Salido, Ignacio Varela
Summary: This study found that 20% of lung cancer patients exhibit ARID2 protein loss, which leads to chromatin structural changes, enhanced cell proliferation and metastasis, and impaired DNA repair, increasing sensitivity to DNA-damaging agents. These findings suggest that ARID2 is a potential tumor suppressor gene and therapeutic target in lung cancer.
Review
Genetics & Heredity
Ana Herrero, Piero Crespo
Summary: Signals transmitted through the RAS-ERK pathway play a crucial role in cancer-related cellular processes. RAS dimerization, especially at membrane microdomains, is essential for RAF activation and can be targeted pharmacologically to prevent tumorigenesis.
Article
Biochemistry & Molecular Biology
L. Francisco Lorenzo-Martin, Mauricio Menacho-Marquez, Natalia Fernandez-Parejo, Sonia Rodriguez-Fdez, Gloria Pascual, Antonio Abad, Piero Crespo, Mercedes Dosil, Salvador A. Benitah, Xose R. Bustelo
Summary: Research shows that Rho GTPases control different aspects of skin stem cells, and their upstream regulators Vav2 and Vav3 affect the number, functional status, and responsiveness of hair follicle bulge stem cells under normal and tumorigenic conditions. These findings highlight the role of these regulators in normal and tumor epidermal stem cells.
Article
Multidisciplinary Sciences
Adam Byron, Billie G. C. Griffith, Ana Herrero, Alexander E. P. Loftus, Emma S. Koeleman, Linda Kogerman, John C. Dawson, Niamh McGivern, Jayne Culley, Graeme R. Grimes, Bryan Serrels, Alex von Kriegsheim, Valerie G. Brunton, Margaret C. Frame
Summary: This study reports the localization of cell adhesion proteins in the nucleus and establishes a nucleo-adhesome, demonstrating their role in transcriptional control. It provides experimental evidence for the cooperation of nuclear adhesion proteins in regulating gene expression.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Marta Morante, Atanasio Pandiella, Piero Crespo, Ana Herrero
Summary: Metastatic melanoma is an immunogenic tumor with poor survival rates, being targeted by immune checkpoint inhibitors. Despite improvements in overall survival rates, melanoma cells develop resistance mechanisms. The combination of RAS-ERK pathway inhibitors and ICI therapy shows promising advantages for treatment.
Article
Multidisciplinary Sciences
Ana Martin-Vega, Laura Ruiz-Peinado, Rocio Garcia-Gomez, Ana Herrero, Dalia de la Fuente-Vivas, Swetha Parvathaneni, Ruben Caloto, Marta Morante, Alex von Kriegsheim, Xose R. Bustelo, David B. Sacks, Berta Casar, Piero Crespo
Summary: RAS-ERK pathway signals are regulated by scaffold proteins, and it is revealed that scaffold proteins can interact with each other and undergo phosphorylation reactions. The trans-phosphorylation process participates in KSR1-regulated adipogenesis and the cytotoxicity exhibited by KSR-directed inhibitors. This finding has implications in signaling and the design of scaffold protein-aimed therapeutics.
Article
Biochemistry & Molecular Biology
Lorena Agudo-Ibanez, Marta Morante, Lucia Garcia-Gutierrez, Andrea Quintanilla, Javier Rodriguez, Alberto Munoz, Javier Leon, Piero Crespo
Summary: The transcription factor MYC is regulated by the kinase activity of ERK2 and plays a role in cell proliferation, transformation, and survival. ERK2 was found to directly regulate MYC transcription by binding to the MYC promoter. ERK2 increased MYC expression and protein abundance in the nucleus, independent of its kinase activity, through interactions with CDK9. These findings demonstrate a kinase-independent role for ERK2 in promoting MYC expression by anchoring CDK9 to the MYC promoter.