Review
Biochemistry & Molecular Biology
Tianmu Wen, Narendra Thapa, Vincent L. Cryns, Richard A. Anderson
Summary: Cytoplasmic phosphoinositides (PI) are crucial regulators of cellular functions. The metabolic cycle of different PI species plays a key role in their regulatory function. This review focuses on the evidence that scaffold proteins regulate the PI3K/Akt pathway in different membrane structures, challenging the belief that plasma membrane is the main site for PI3k/Akt signaling.
Article
Cell Biology
Wen Li, Yulan Li, Yetong Guan, Yingxin Du, Mingsheng Zhao, Xiaotong Chen, Faliang Zhu, Chun Guo, Yufeng Jia, Yuan Li, Xiaoyu Wang, Xiaoyan Wang, Yongyu Shi, Qun Wang, Yan Li, Lining Zhang
Summary: Autophagy is a conserved evolutionary process closely integrated with the immune system to modulate immune responses through cell signaling pathways. TNFAIP8L2, a newly identified immune negative regulator, plays a crucial role in regulating autophagy by interacting with RAC1-MTORC1 axis.
Article
Medicine, Research & Experimental
Reini E. N. van der Welle, Rebekah Jobling, Christian Burns, Paolo Sanza, Jan A. van der Beek, Alfonso Fasano, Lan Chen, Fried J. Zwartkruis, Susan Zwakenberg, Edward F. Griffin, Corlinda ten Brink, Tineke Veenendaal, Nalan Liv, Conny M. A. van Ravenswaaij-Arts, Henny H. Lemmink, Rolph Pfundt, Susan Blaser, Carolina Sepulveda, Andres M. Lozano, Grace Yoon, Teresa Santiago-Sim, Cedric S. Asensio, Guy A. Caldwell, Kim A. Caldwell, David Chitayat, Judith Klumperman
Summary: Mutations in VPS41 disrupt HOPS function, interfere with the TFEB/TFE3 axis of mTORC1 signaling, and result in a neurodegenerative disease.
EMBO MOLECULAR MEDICINE
(2021)
Editorial Material
Cell Biology
Matthew J. Eramo, Rajendra Gurung, Christina A. Mitchell, Meagan J. McGrath
Summary: Autophagic lysosome reformation (ALR) is crucial for recycling autophagy membranes to form lysosomes. INPP5K, an enzyme that converts PtdIns(4,5)P-2 to PtdIns4P, plays a key role in this process in skeletal muscle. Mutations in INPP5K can lead to muscular dystrophy by disrupting ALR and lysosome homeostasis in muscles.
Editorial Material
Cell Biology
Alessandro Luciani, Olivier Devuyst
Summary: This study identified the role of CTNS deficiency in triggering dedifferentiation and dysfunction of PT cells, leading to kidney disease and metabolic complications. It was found that CTNS deficiency stimulates activation of the MTORC1 pathway, diverting cell trajectories towards growth and proliferation, disrupting homeostasis and specialized functions. Treatment with low doses of rapamycin can correct lysosome function and differentiation, ameliorating PT dysfunction in preclinical models of cystinosis.
Article
Multidisciplinary Sciences
Kaushal Asrani, Juhyung Woo, Adrianna A. Mendes, Ethan Schaffer, Thiago Vidotto, Clarence Rachel Villanueva, Kewen Feng, Lia Oliveira, Sanjana Murali, Hans B. Liu, Daniela C. Salles, Brandon Lam, Pedram Argani, Tamara L. Lotan
Summary: The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. However, the authors found that in renal cells with TSC2 loss, TFEB is paradoxically hypophosphorylated and activated due to impaired lysosomal recruitment of the FLCN:FNIP2 complex.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Yunpeng Bai, Guimei Yu, Hong-Ming Zhou, Ovini Amarasinghe, Yuan Zhou, Peipei Zhu, Qinglin Li, Lujuan Zhang, Frederick Nguele Meke, Yiming Miao, Eli Chapman, W. Andy Tao, Zhong-Yin Zhang
Summary: Overexpression of PTP4A phosphatases is associated with advanced cancers and their biological functions are not fully understood. In this study, we identified VCP/p97 as a substrate of PTP4A2. PTP4A2 dephosphorylates VCP at Tyr805, allowing the association of VCP with its cofactors in the ELDR complex, which is involved in lysophagy and lysosomal homeostasis. Deletion of Ptp4a2 disrupts lysosomal homeostasis and impairs recovery from acute kidney injury.
Editorial Material
Cell Biology
Ying Yang, Daniel J. Klionsky
Summary: This study reveals that under glucose starvation, AMPK activates ULK1 to regulate the phosphorylation of PIKFYVE, leading to increased formation of PtdIns5P-containing autophagosomes and upregulation of autophagy. This novel discovery not only expands our understanding of autophagy but also provides insights into potential therapeutic strategies for glucose-related disorders.
Article
Biotechnology & Applied Microbiology
Yang Doris Liu, Jun He, Weiying Luan, Yanfeng Xu, Qianqian Li, Lishan Pan, Jianguo Liu
Summary: Research indicates that natural astaxanthin protects kidney function and subcellular structure by promoting autophagy and lysosomal detoxification pathways.
ALGAL RESEARCH-BIOMASS BIOFUELS AND BIOPRODUCTS
(2023)
Article
Biochemistry & Molecular Biology
Delong Meng, Qianmei Yang, Chase H. Melick, Brenden C. Park, Ting-Sung Hsieh, Adna Curukovic, Mi-Hyeon Jeong, Junmei Zhang, Nicholas G. James, Jenna L. Jewell
Summary: The study identified ADP-ribosylation factor GTPase-activating protein 1 (ArfGAP1) as a critical regulator of mTORC1, which inhibits cell growth through preventing the lysosomal transport and activation of mTORC1, and is also an independent prognostic factor for the overall survival of pancreatic cancer patients.
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
Jennifer J. Lee, Vaibhav Jain, Ravi K. Amaravadi
Summary: Despite advances in targeted therapy and immunotherapy, treating RAS mutant cancers remains challenging. These cancers have been found to activate adaptive resistance mechanisms like autophagy during MAPK inhibition. Recent focus has been on developing MAPK pathway and autophagy inhibitors for potential synthetic lethal approaches in cancer therapy, with ongoing clinical trials to evaluate their efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Biochemistry & Molecular Biology
Dohun Kim, Gerta Hoxhaj
Summary: Jouandin et al. (2022) demonstrate that lysosomal-derived cysteine functions as a signal to enhance the tricarboxylic acid (TCA) cycle and suppress TORC1 signaling, allowing Drosophila to withstand periods of starvation.
Article
Cell Biology
Li Xia, Tiejian Nie, Fangfang Lu, Lu Huang, Xiaolong Shi, Dongni Ren, Jianjun Lu, Xiaobin Li, Tuo Xu, Bozhou Cui, Qing Wang, Guodong Gao, Qian Yang
Summary: This study discovered a transcriptional regulatory mechanism of MTORC1 involving MEF2A and MEF2D. MEF2A and MEF2D control the cyto-lysosome shutting of MTORC1 by regulating the transcription of FNIP1 and FNIP2, and tyrosine phosphorylation of MEF2D by SRC/c-Src enhances its transcriptional activity and is necessary for MTORC1 activation. The protein and tyrosine phosphorylation levels of MEF2D are elevated in pancreatic cancer and positively correlated with MTORC1 activity.
Article
Biochemistry & Molecular Biology
Anand Ramaian Santhaseela, Tamilselvan Jayavelu
Summary: Research has shown that mTORC1 is localized to lysosomes during its activation, but the biological significance of this remains unclear. The localization of lysosomes themselves is also influenced under conditions affecting mTORC1 activity, suggesting a potential interconnection between mTORC1 and lysosome in regulating autophagy. This opens up a new avenue for understanding autophagy regulation, with its complete mechanistic insights yet to be determined.
Article
Medicine, Research & Experimental
Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kano, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger
JOURNAL OF CLINICAL INVESTIGATION
(2016)
Editorial Material
Biochemistry & Molecular Biology
Archna Ravi, Brooke M. Emerling
Article
Biochemistry & Molecular Biology
Mark R. Lundquist, Marcus D. Goncalves, Ryan M. Loughran, Elite Possik, Tarika Vijayaraghavan, Annan Yang, Chantal Pauli, Archna Ravi, Akanksha Verma, Zhiwei Yang, Jared L. Johnson, Jenny C. Y. Wong, Yilun Ma, Katie Seo-Kyoung Hwang, David Weinkove, Nullin Divecha, John M. Asara, Olivier Elemento, Mark A. Rubin, Alec C. Kimmelman, Arnim Pause, Lewis C. Cantley, Brooke M. Emerling
Article
Oncology
Seong M. Kim, Tricia T. Nguyen, Archna Ravi, Peter Kubiniok, Brendan T. Finicle, Vaishali Jayashankar, Leonel Malacrida, Jue Hou, Jane Robertson, Dong Gao, Jonathan Chernoff, Michelle A. Digman, Eric O. Potma, Bruce J. Tromberg, Pierre Thibault, Aimee L. Edinger
Article
Cell Biology
Shelly Kaushik, Archna Ravi, Feroz M. Hameed, Boon Chuan Low
Article
Biochemistry & Molecular Biology
Archna Ravi, Shelly Kaushik, Aarthi Ravichandran, Catherine Qiurong Pan, Boon Chuan Low
JOURNAL OF BIOLOGICAL CHEMISTRY
(2015)
Editorial Material
Cell Biology
Mike F. Renne, Brooke M. Emerling
JOURNAL OF CELL BIOLOGY
(2020)
Article
Cell Biology
Archna Ravi, Lavinia Palamiuc, Ryan M. Loughran, Joanna Triscott, Gurpreet K. Arora, Avi Kumar, Vivian Tieu, Chantal Pauli, Matthias Reist, Rachel J. Lew, Shauna L. Houlihan, Christof Fellmann, Christian Metallo, Mark A. Rubin, Brooke M. Emerling
Summary: PI5P4Ks phosphorylate PI-5-P to PI-4,5-P2 and play a critical role in maintaining energy balance by regulating lipid trafficking and mitochondrial metabolism; Loss of PI5P4Ks leads to mitochondrial structural and functional abnormalities, exacerbated under nutrient deprivation, ultimately causing cell death; Inhibiting PI5P4Ks results in decreased cell viability in cancer cells and suppressed tumor growth in mouse models.
DEVELOPMENTAL CELL
(2021)
Review
Biochemistry & Molecular Biology
Gurpreet K. Arora, Lavinia Palamiuc, Brooke M. Emerling
Summary: Cancer cells adapt to microenvironmental stresses but also have vulnerabilities that can be targeted for therapy. PI5P4Ks, a family of stress-regulated kinases, are essential for metabolic adaptation in cancer cells and have a synthetic lethal interaction with the tumor suppressor p53. Understanding the role of PI5P4Ks in cancer signaling has led to the development of specific inhibitors for potential therapeutic interventions.
Article
Oncology
Chantal Pauli, Lamberto De Boni, Jonathan E. Pauwels, Yanjiang Chen, Lara Planas-Paz, Reid Shaw, Brooke M. Emerling, Carla Grandori, Benjamin D. Hopkins, Mark A. Rubin
Summary: In this study, a functional precision oncology approach was implemented to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibro-sarcoma. Comprehensive genomic profiling and high-throughput drug screening were used to identify therapeutic options and validate them in patient-derived xenograft models. Targeting the cell cycle was found to be a powerful approach in these tumors.
MOLECULAR CANCER RESEARCH
(2022)
Article
Cell Biology
Archna Ravi, Lavinia Palamiuc, Brooke M. Emerling
Summary: While organelles are individual compartments with specialized functions, inter-organelle communication is essential for cellular homeostasis. This communication is mediated by phospholipids on organelle membranes, particularly phosphoinositides like phosphatidylinositol 4,5-bisphosphate (PI-4,5-P-2). This review focuses on the role of non-canonical Type II PIPKs in generating PI-4,5-P-2 and their impact on organelle crosstalk, cellular health, and human diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Biotechnology & Applied Microbiology
John E. Burke, Joanna Triscott, Brooke M. Emerling, Gerald R. Hammond
Summary: This Review describes the structure, function, regulation, and disease roles of clinically relevant PIKs outside of class I PI3Ks, as well as the development of potent and specific small-molecule inhibitors. Phosphoinositide kinases are master regulators of cellular processes and their dysregulation has been implicated in various human diseases. Recent years have seen increased interest in targeting phosphoinositide kinases beyond class I PI3Ks, leading to the clinical development of selective inhibitors. This comprehensive analysis provides an overview of the current understanding and progress in the development of phosphoinositide kinase inhibitors.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Biochemical Research Methods
Alexandra M. Amen, Ryan M. Loughran, Chun-Hao Huang, Rachel J. Lew, Archna Ravi, Yuanzhe Guan, Emma M. Schatoff, Lukas E. Dow, Brooke M. Emerling, Christof Fellmann
Summary: Multi-miR is a microRNA-embedded shRNA system that allows simultaneous expression of multiple shRNAs, resulting in robust RNA interference. The developed all-in-one vectors show high sensitivity to activation and resistance to inactivation. This system is demonstrated to be effective in intracranial expression of shRNAs in a glioblastoma model and in abolishing tumor growth in a mouse model of KRAS-mutant cancer through combinatorial synthetic lethality.
CELL REPORTS METHODS
(2022)