Editorial Material
Cell Biology
Lidia Wrobel, Sandra M. Hill, Avraham Ashkenazi, David C. Rubinsztein
Summary: VCP protein plays a role in promoting autophagosome biogenesis by regulating the levels of PtdIns3P, stabilizing autophagy-related proteins through interactions with ATXN3 and the PtdIns3K complex.
Article
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Mohammad-Javad Sanaei, Atieh Pourbagheri-Sigaroodi, Davood Bashash
Summary: Lipid signaling refers to the biological process in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. The family of phosphoinositide 3-kinase (PI3K) plays a crucial role in this pathway, affecting various aspects of cellular biology such as cell survival, proliferation, migration, endocytosis, intracellular trafficking, metabolism, and autophagy. Different classes of PI3Ks have been identified in yeast and mammals, with class I PI3Ks being extensively studied in cancer biology. Abnormal activation of class I PI3Ks has been implicated in human tumors, particularly through activating mutations in the PIK3CA gene. Class II and III PI3Ks are involved in regulating vesicle trafficking and autophagy processes. This review aims to discuss the latest research findings on PI3Ks-mediated cell biological processes and explore the mechanisms by which different types of phosphoinositides derived from PI3Ks act.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Chien-An Chu, Yi-Wen Wang, Yi-Lin Chen, Hui-Wen Chen, Jing-Jing Chuang, Hong-Yi Chang, Chung-Liang Ho, Chen Chang, Nan-Haw Chow, Chung-Ta Lee
Summary: PIK3C3, as a member of the PI3K family, plays a critical role in autophagy and tumor development. Inhibition of PIK3C3 can suppress autophagy and affect tumor cell proliferation, growth, and invasion. Discovery of pharmacological inhibitors targeting PIK3C3 may provide new strategies for improving treatment outcomes in PIK3C3-mediated diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Yohei Ohashi
Summary: Phosphatidylinositol-3-phosphate plays a crucial role in cell survival, primarily involved in autophagy and endocytic pathways. Developing highly selective drugs targeting specific VPS34/Vps34 complexes is essential for treating diseases associated with autophagy defects.
Article
Multidisciplinary Sciences
Qixia Xue, Chen Shen, Qianwen Liu, Peng Liu, Da Guo, Lihua Zheng, Jinling Liu, Chang Liu, Qinyi Ye, Tao Wang, Jiangli Dong
Summary: This study discovered the involvement of myotubularin phosphatase in autophagy in plants, particularly in the process of symbiotic nitrogen fixation.
Article
Chemistry, Medicinal
Xue-Mei Zheng, Yuan-Si Chen, Yu-Juan Ban, Yu-Jie Wang, Yong-Xi Dong, Li Lei, Bing Guo, Jian-Ta Wang, Lei Tang, Hong-Liang Li, Ji-Quan Zhang
Summary: In this study, a series of substituted benzoxazole derivatives were designed and synthesized. The compound 18a showed higher inhibitory activity against PI3Kα and better anti-cancer effects, as well as improved selectivity and pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Milton Osmar Aguilera, Esteban Robledo, Mariana Melani, Pablo Wappner, Maria Isabel Colombo
Summary: In this article, the protein FKBP38 is reported to be a novel modulator of the initial steps of the autophagic pathway, specifically in starvation-induced autophagy. FKBP38 interacts with the VPS34 lipid kinase complex, with the transmembrane domain of FKBP38 being critical for its biological function.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Article
Pharmacology & Pharmacy
Zhoupeng Li, Fang Wang, Yongsheng Liu, Dongshen Zhai, Xiaoxiao Zhang, Qikang Ying, Min Jia, Xiaoyan Xue, Jingru Meng, Jing Li, Xingan Wu, Mingkai Li
Summary: A study found that the coumarin derivative N6 shows strong inhibitory effects on HTNV, and early administration can effectively inhibit virus replication and production. Molecular docking results show that N6 interacts with key amino acid residues, and the treatment can inhibit the expression of specific proteins.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Cell Biology
Anthony Ravussin, Andreas Brech, Sharon A. Tooze, Harald Stenmark
Summary: The study reveals the key role of the phosphatidylinositol 3-phosphate-binding protein SNX4 in membrane protein recycling from endolysosomes and proper autophagic flux. SNX4 mediates the recycling of lipid scramblase ATG9A, contributing to the expansion of nascent autophagosome membranes and sustaining autophagy.
JOURNAL OF CELL SCIENCE
(2021)
Review
Cell Biology
Katlynn Bugda Gwilt, Jay R. Thiagarajah
Summary: The development of cell polarity in epithelia is crucial for tissue morphogenesis and transport between the environment and the underlying tissue. Membrane lipids, especially phosphoinositide species, play a primary role in generating epithelial polarity by influencing membrane lipid distribution and protein localization and vesicular trafficking.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Ujjwala Karmacharya, Jong-Wha Jung
Summary: Autophagy is a cellular process that removes damaged components of cells and recycles them as biochemical building blocks. Dysregulation of autophagy has been linked to various diseases, including cancer. In recent years, targeting Unc-51-like autophagy-activating kinase (ULK) inhibitors has emerged as a promising strategy for cancer treatment. This review highlights the recent discoveries and developments in small-molecule ULK inhibitors and their potential as anticancer agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Yuta Shimanaka, Keiko Matsumoto, Yuki Tanaka, Yuki Ishino, Shenwei Ni, Jun-Lin Guan, Hiroyuki Arai, Nozomu Kono
Summary: Phosphoinositide species, with different phosphorylation patterns, participate in various cellular events. A newly developed chromatography-mass spectrometry method allows for quantification of all seven phosphoinositide regioisomers, facilitating research on their physiological and pathological roles. Further improvements are needed for absolute quantification of minor phosphoinositide regioisomers in biological samples.
COMMUNICATIONS CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xiaobing Zhang, Songsong Dan, Xiao Pan, Jingchao Li, Qucheng Wei, Liming Huang, Bo Kang, Cheng Chen
Summary: Intrinsic or acquired chemoresistance is a major challenge in cancer treatment. Aberrantly strengthened DNA repair is a common mechanism leading to drug resistance, and targeting DNA repair system in cancer cells can overcome chemoresistance. This study discovered that the endonuclease FEN1 interacts with PI(3)P and its functionality is crucial for repairing DNA damage. In addition, the PI(3)P synthesizing enzyme VPS34 is negatively associated with patients' survival, and inhibiting VPS34 sensitizes chemoresistant cancer cells. These findings provide a potential strategy for counteracting chemoresistance by targeting the VPS34-PI(3)P-mediated DNA repair pathway.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Daniel Pokorny, Linda Truebestein, Kaelin D. Fleming, John E. Burke, Thomas A. Leonard
Summary: The activation of Sgk3 is regulated by phosphatidylinositol 3-phosphate (PI3P) downstream of growth factor signaling via class I phosphatidylinositol 3-kinase (PI3K) signaling and by class III PI3K/Vps34-mediated PI3P production on endosomes. This activation is controlled by a combination of phosphorylation and allosteric activation, with PI3P inducing conformational changes in Sgk3 via its PX domain, leading to activation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Immunology
Ebru Aydin, Sebastian Faehling, Mariam Saleh, Laura Llao Cid, Martina Seiffert, Philipp M. Roessner
Summary: PI3K pathway plays a crucial role in cell growth and malignant transformation, with its hyperactivation being a hallmark of cancer. Inhibiting PI3K not only affects cancer cells but also impacts the tumor microenvironment and immune cell function. Understanding the effects of PI3K inhibition on the tumor microenvironment in CLL can lead to improved drug development and novel combinatory treatment strategies.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Yohei Ohashi, Shirley Tremel, Roger L. Williams
JOURNAL OF LIPID RESEARCH
(2019)
Article
Multidisciplinary Sciences
N. Tsolakos, T. N. Durrant, T. Chessa, S. M. Suire, D. Oxley, S. Kulkarni, J. Downward, O. Perisic, R. L. Williams, L. Stephens, P. T. Hawkins
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Multidisciplinary Sciences
Alison J. Inglis, Glenn R. Masson, Sichen Shao, Olga Perisic, Stephen H. McLaughlin, Ramanujan S. Hegde, Roger L. Williams
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Multidisciplinary Sciences
Madhanagopal Anandapadamanaban, Glenn R. Masson, Olga Perisic, Alex Berndt, Jonathan Kaufman, Chris M. Johnson, Balaji Santhanam, Kacper B. Rogala, David M. Sabatini, Roger L. Williams
Article
Medicine, Research & Experimental
Glenn R. Masson, Roger L. Williams
COLD SPRING HARBOR PERSPECTIVES IN MEDICINE
(2020)
Article
Biology
Heather P. Harding, Adriana Ordonez, Felicity Allen, Leopold Parts, Alison J. Inglis, Roger L. Williams, David Ron
Article
Biology
Yohei Ohashi, Shirley Tremel, Glenn Robert Masson, Lauren McGinney, Jerome Boulanger, Ksenia Rostislavleva, Christopher M. Johnson, Izabella Niewczas, Jonathan Clark, Roger L. Williams
Article
Cell Biology
Yohei Ohashi, Shirley Tremel, Roger L. Williams
Summary: Phosphatidylinositol-3-phosphate (PtdIns3P) plays a crucial role in autophagosome formation and endocytic trafficking regulation, with the activities of human PIK3C3/VPS34-containing complexes I and II being significantly influenced by membrane physicochemical parameters such as lipid unsaturation, curvature, and negative charge. The interaction of these complexes with membranes, specifically the presence of unsaturated lipids, membrane curvature, and negatively charged phospholipids, is essential for regulating their kinase activity and ultimately their function in autophagy and endocytosis.
Article
Multidisciplinary Sciences
Shirley Tremel, Yohei Ohashi, Dustin R. Morado, Jessie Bertram, Olga Perisic, Laura T. L. Brandt, Marie-Kristin von Wrisberg, Zhuo A. Chen, Sarah L. Maslen, Oleksiy Kovtun, Mark Skehel, Juri Rappsilber, Kathrin Lang, Sean Munro, John A. G. Briggs, Roger L. Williams
Summary: The lipid phosphatidylinositol-3-phosphate (PI3P) acts as a regulator of endocytosis and autophagy, generated by two complexes containing the lipid kinase VPS34. Rab5 and Rab1a GTPases recruit and activate specific VPS34 complexes on membranes through unique binding interfaces, guiding them to distinct cellular locations. Insights into the recruitment and activation mechanisms of VPS34 complexes by specific Rab GTPases are provided through biochemical and structural analyses.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Anna C. Howes, Olga Perisic, Roger L. Williams
Summary: This study determined the structure of H2O2-activated ATM using cryo-EM, revealing the structural remodeling and active site optimization that occur during oxidative activation of ATM. The captured substrate binding also provides insights into the mechanism of ATM activation during oxidative stress.
Article
Biochemistry & Molecular Biology
Natalie K. Rynkiewicz, Karen E. Anderson, Sabine Suire, Daniel M. Collins, Eleftherios Karanasios, Oscar Vadas, Roger Williams, David Oxley, Jonathan Clark, Len R. Stephens, Phillip T. Hawkins