Article
Biology
Dario Cilleros-Rodriguez, Raquel Martin-Morales, Pablo Barbeito, Abhijit Deb Roy, Abdelhalim Loukil, Belen Sierra-Rodero, Gonzalo Herranz, Olatz Pampliega, Modesto Redrejo-Rodriguez, Sarah C. Goetz, Manuel Izquierdo, Takanari Inoue, Francesc R. Garcia-Gonzalo
Summary: Primary cilia are membrane protrusions responsible for sensory functions, and dysfunction of these cilia can lead to ciliopathies. INPP5E, a phosphoinositide phosphatase, is mutated in ciliopathies such as Joubert syndrome. This study uncovers the mechanism of INPP5E ciliary targeting and interactions, providing valuable insights into ciliary functions and related disorders.
Article
Cell Biology
Lena Bruecker, Stefanie Kornelia Becker, Vanessa Maissl, Gregory Harms, Maddy Parsons, Helen Louise May-Simera
Summary: Primary cilia are important for cellular communication and defects in cilia development or function are associated with genetic disorders. Recent research suggests that ciliary proteins are involved in actin regulation, but the exact nature of their interconnection is not fully understood.
JOURNAL OF MOLECULAR CELL BIOLOGY
(2023)
Review
Cell Biology
Huijie Zhao, Ziam Khan, Christopher J. Westlake
Summary: Ciliogenesis is a complex process involved in the assembly of cilia and flagella, which are essential for cell motility and signaling. Membrane trafficking regulators play a crucial role in ciliogenesis by organizing membranes around microtubule-based structures. The association of membranes with the distal end of the centriole is a critical step in initiating ciliogenesis. This review focuses on recent insights into cilia biogenesis and the roles of membrane trafficking regulators in ciliogenesis mechanisms relevant to human disease.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2023)
Article
Clinical Neurology
Huixuan Yue, Shen Li, Jiaxing Qin, Tingting Gao, Jianjun Lyu, Yu Liu, Xiuwei Wang, Zhen Guan, Zhiqiang Zhu, Bo Niu, Rugang Zhong, Jin Guo, Jianhua Wang
Summary: The study revealed that the Inpp5e gene is closely related to ciliogenesis during embryonic neurodevelopment and its down-regulation under conditions of inositol deficiency may lead to abnormal cilia formation.
FRONTIERS IN NEUROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Anja Nitzsche, Riikka Pietila, Dominic T. Love, Chiara Testini, Takeshi Ninchoji, Ross O. Smith, Elisabet Ekvarn, Jimmy Larsson, Francis P. Roche, Isabel Egana, Suvi Jauhiainen, Philipp Berger, Lena Claesson-Welsh, Mats Hellstrom
Summary: Cell signalling is tightly regulated by specialized membranes and vesicles containing unique lipids and proteins. Paladin, identified as a PI(4,5)P-2 phosphatase, regulates VEGFR2 endosomal signalling and angiogenesis by interacting with VEGFR2 in endosomal and Golgi compartments. Inhibition of Paladin could potentially modulate VEGFR2 signalling and angiogenesis without directly inhibiting the receptor.
Article
Biochemistry & Molecular Biology
Ali S. Sharif, Cecilia D. Gerstner, Martha A. Cady, Vadim Y. Arshavsky, Christina Mitchell, Guoxin Ying, Jeanne M. Frederick, Wolfgang Baehr
Summary: INPP5E, also known as pharbin, is a phosphatidylinositol polyphosphate 5-phosphatase that modulates membrane composition and is crucial for ciliary function. Mutations in INPP5E can lead to syndromic ciliopathies such as Joubert syndrome. Loss of INPP5E in the retina specifically results in rapid rod-cone degeneration resembling Leber congenital amaurosis, with defects in axonemal structure and disc membranes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Toshio Nakajima, Shun Hosoyamada, Takehiko Kobayashi, Yukio Mukai
Summary: The study reveals that APases in yeast are crucial for maintaining normal replicative lifespan. Deletion of all four APase genes shortened lifespan in yeast strains, but the issue was resolved with modification of other genes. This indicates that yeast APases modulate replicative lifespan by dephosphorylation of intracellular IP6.
Article
Biochemistry & Molecular Biology
Bart Appelhof, Matias Wagner, Julia Hoefele, Anja Heinze, Timo Roser, Margarete Koch-Hogrebe, Stefan D. Roosendaal, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Erin Torti, Henry Houlden, Reza Maroofian, Farrah Rajabi, Heinrich Sticht, Frank Baas, Dagmar Wieczorek, Rami Abou Jamra
Summary: This study describes eight children with Pontocerebellar hypoplasia (PCH) from four unrelated families carrying homozygous variants in the MINPP1 gene. These variants result in either a complete absence of MINPP1, impaired protein folding, destabilization of protein structure or reduction in protein stability, leading to the pathogenesis of the disease. This study presents MINPP1 as a novel autosomal recessive gene associated with PCH.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2021)
Review
Cell Biology
Nan-Xi Zheng, Ya-Ting Miao, Xi Zhang, Mu-Zhi Huang, Muhammad Jahangir, Shilin Luo, Bing Lang
Summary: Cilium is a conserved antenna-like structure on mammalian cells, and dysfunctional primary cilia are associated with various congenital diseases. Intraflagellar transport (IFT) is essential for maintaining cilia function, and disrupted IFT contributes to ciliopathies. IFT172 is a newly identified protein related to rare ciliopathies such as MZSDS and BBS, and this review summarizes its genetic and protein characteristics and its role in intraflagellar transport.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Cell Biology
Toneisha Stubbs, James I. Bingman, Jason Besse, Kirk Mykytyn
Summary: Primary cilia are important for neuronal functions and their dysfunction is linked to ciliopathies. Bardet-Biedl syndrome proteins play a crucial role in trafficking G protein-coupled receptors (GPCRs) in neuronal cilia, and their absence leads to abnormal localization of signaling proteins in the brain.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Oncology
Jun Deng, Xu Lin, Qi Li, Xiao-yu Cai, Lin-wen Wu, Wei Wang, Bo Zhang, Yang-ling Li, Jian Hu, Neng-ming Lin
Summary: The study revealed that INPP5B is decreased in LUAD tissues and its low expression is associated with advanced pathological features. Furthermore, INPP5B was identified as a significant independent prognostic and diagnostic factor for LUAD patients. Experimental findings demonstrated that INPP5B inhibits LUAD cell proliferation and migration by regulating the activity of the PTEN and PI3K/AKT signaling pathways.
CANCER CELL INTERNATIONAL
(2022)
Article
Neurosciences
Toneisha Stubbs, Andrew Koemeter-Cox, James I. Bingman, Fangli Zhao, Anuradha Kalyanasundaram, Leslie A. Rowland, Muthu Periasamy, Calvin S. Carter, Val C. Sheffield, Candice C. Askwith, Kirk Mykytyn
Summary: A rod-shaped appendage called a primary cilium projects from most central neurons in the mammalian brain. Cilia are important for neuronal signaling and their dysfunction is associated with various neuropathologies. This study demonstrates that disrupting the localization of a specific ciliary GPCR, called dopamine receptor 1 (D-1), in neurons leads to obesity and reduced locomotor activity in male and female mice. Loss of a BBS protein or cilia on D-1-expressing neurons also reduces D-1-mediated signaling. These findings highlight the importance of neuronal cilia for proper GPCR signaling and shed light on the role of cilia in regulating weight and locomotor activity.
JOURNAL OF NEUROSCIENCE
(2022)
Review
Immunology
Guy Tran Van Nhieu, Patricia Latour-Lambert, Jost Enninga
Summary: Shigella's type III effector IpgD plays a key role in disrupting the cortical actin filaments of epithelial cells by decreasing PI4,5P(2) levels, facilitating bacterial invasion and cell migration. Additionally, IpgD also stimulates various signaling pathways and regulates endosomal trafficking and immune responses, making it a versatile bacterial enzyme.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Cell Biology
Dang Minh Tran, Nozomu Yoshioka, Norihisa Bizen, Yukiko Mori-Ochiai, Masato Yano, Shogo Yanai, Junya Hasegawa, Satoshi Miyashita, Mikio Hoshino, Junko Sasaki, Takehiko Sasaki, Hirohide Takebayashi
Summary: Phosphoinositides (PIPs) are important intracellular signaling molecules that regulate various cellular processes. Abnormalities in PIP metabolism can lead to various pathological conditions, including neurological diseases. Mutations in INPP4A, which encodes a phosphoinositide phosphatase, have been found to cause neurological diseases with diverse phenotypes. The study found that different Inpp4a mutant mice strains exhibited distinct cerebellar phenotypes, which may be due to varying protein expression levels and phosphatase activity of different Inpp4a variants. These findings provide insights into the role of INPP4A mutations in disease pathogenesis and have potential implications for personalized therapy.
DISEASE MODELS & MECHANISMS
(2023)
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.
Article
Biochemistry & Molecular Biology
Sarah E. Conduit, Elizabeth M. Davies, Lisa M. Ooms, Rajendra Gurung, Meagan J. McGrath, Sandra Hakim, Denny L. Cottle, Ian M. Smyth, Jennifer M. Dyson, Christina A. Mitchell
HUMAN MOLECULAR GENETICS
(2020)
Article
Cell Biology
Jessica L. Teo, Guillermo A. Gomez, Saroja Weeratunga, Elizabeth M. Davies, Ivar Noordstra, Srikanth Budnar, Hiroko Katsuno-Kambe, Meagan J. McGrath, Suzie Verma, Vanesa Tomatis, Bipul R. Acharya, Lakshmi Balasubramaniam, Rachel M. Templin, Kerrie-Ann Mcmahon, Yoke Seng Lee, Robert J. Ju, Samantha J. Stebhens, Benoit Ladoux, Christina A. Mitchell, Brett M. Collins, Robert G. Parton, Alpha S. Yap
DEVELOPMENTAL CELL
(2020)
Review
Biochemistry & Molecular Biology
Sarah E. Conduit, Bart Vanhaesebroeck
BIOCHEMICAL JOURNAL
(2020)
Article
Biochemistry & Molecular Biology
Hon Yan K. Yip, Annabel Chee, Ching-Seng Ang, Sung-Young Shin, Lisa M. Ooms, Zainab Mohammadi, Wayne A. Phillips, Roger J. Daly, Timothy J. Cole, Roderick T. Bronson, Lan K. Nguyen, Tony Tiganis, Robin M. Hobbs, Catriona A. McLean, Christina A. Mitchell, Antonella Papa
Article
Multidisciplinary Sciences
Nuthasuda Srijakotre, Heng-jia Liu, Max Nobis, Joey Man, Hon Yan Kelvin Yip, Antonella Papa, Helen E. Abud, Kurt I. Anderson, Heidi C. E. Welch, Tony Tiganis, Paul Timpson, Catriona A. McLean, Lisa M. Ooms, Christina A. Mitchell
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2020)
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.
Article
Biochemistry & Molecular Biology
Laura D'Andrea, Christina M. Lucato, Elsa A. Marquez, Yong-Gang Chang, Srgjan Civciristov, Chantel Mastos, Christopher J. Lupton, Cheng Huang, Hans Elmlund, Ralf B. Schittenhelm, Christina A. Mitchell, James C. Whisstock, Michelle L. Halls, Andrew M. Ellisdon
Summary: The PTEN:P-Rex2 complex assembly inhibits the activity of both proteins and dysregulation can drive PI3K-AKT signaling and cellular proliferation. The study revealed the interactions between PTEN and P-Rex2, proposing a class of gain-of-function mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.
Article
Cell Biology
Sarah E. Conduit, Elizabeth M. Davies, Alex J. Fulcher, Viola Oorschot, Christina A. Mitchell
Summary: Phosphoinositides are distributed in distinct subregions at the transition zone of primary cilia, with different subtypes forming ring-shaped patterns on the inner transition zone membrane. The phosphoinositide effector kinase and 5-phosphatase are localized in close proximity to these phosphoinositides. INPP5E is likely to be located in a subdomain of the transition zone membrane.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Samuel J. Rodgers, Lisa M. Ooms, Viola M. J. Oorschot, Ralf B. Schittenhelm, Elizabeth Nguyen, Sabryn A. Hamila, Natalie Rynkiewicz, Rajendra Gurung, Matthew J. Eramo, Absorn Sriratana, Clare G. Fedele, Franco Caramia, Sherene Loi, Genevieve Kerr, Helen E. Abud, Georg Ramm, Antonella Papa, Andrew M. Ellisdon, Roger J. Daly, Catriona A. McLean, Christina A. Mitchell
Summary: INPP4B functions as a tumor suppressor in triple negative breast cancer by converting PI(3,4)P-2 to PI(3)P. However, in PIK3CA-mutant ER+ breast cancers, INPP4B enhances cell proliferation and tumor growth by promoting PI3K alpha-dependent late endosome formation and trafficking that activates Wnt/beta -catenin signaling.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Alessia Floerchinger, Kendelle J. Murphy, Sharissa L. Latham, Sean C. Warren, Andrew T. McCulloch, Young-Kyung Lee, Janett Stoehr, Pauline Melenec, Cris S. Guaman, Xanthe L. Metcalf, Victoria Lee, Anaiis Zaratzian, Andrew Da Silva, Michael Tayao, Sonia Rolo, Monica Phimmachanh, Ghazal Sultani, Laura McDonald, Susan M. Mason, Nicola Ferrari, Lisa M. Ooms, Anna-Karin E. Johnsson, Heather J. Spence, Michael F. Olson, Laura M. Machesky, Owen J. Sansom, Jennifer P. Morton, Christina A. Mitchell, Michael S. Samuel, David R. Croucher, Heidi C. E. Welch, Karen Blyth, C. Elizabeth Caldon, David Herrmann, Kurt Anderson, Paul Timpson, Max Nobis
Summary: Assessing drug response within live native tissue provides increased fidelity in optimizing efficacy and minimizing off-target effects. Using single-cell intravital imaging, this study demonstrates that Rac1 inhibition can reduce tumor progression and metastases to improve overall survival in an autochthonous setting. The study also reveals enhanced Rac1 activity of cells near live tumor vasculature, and how Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress for better anti-metastatic response during transit to secondary sites.
Article
Multidisciplinary Sciences
Chrysovalantou E. Xirouchaki, Yaoyao Jia, Meagan J. McGrath, Spencer Greatorex, Melanie Tran, Troy L. Merry, Dawn Hong, Matthew J. Eramo, Sophie C. Broome, Jonathan S. T. Woodhead, Randall F. D'souza, Jenny Gallagher, Ekaterina Salimova, Cheng Huang, Ralf B. Schittenhelm, Junichi Sadoshima, Matthew J. Watt, Christina A. Mitchell, Tony Tiganis
Summary: ROS generated by NOX4 in skeletal muscle play a crucial role in promoting muscle function, maintaining redox balance, and preventing the development of insulin resistance. Reductions in NOX4 levels in skeletal muscle contribute to insulin resistance development, affecting exercise capacity and antioxidant defense mechanisms.
Article
Biochemistry & Molecular Biology
Samuel J. Rodgers, Emily Jones, Senthil Arumugam, Sabryn A. Hamila, Jill Danne, Rajendra Gurung, Matthew J. Eramo, Randini Nanayakkara, Georg Ramm, Meagan J. McGrath, Christina A. Mitchell
Summary: This study reveals an endosome-dependent phosphoinositide pathway that regulates lysosome repopulation during basal autophagy. This pathway involves the sequential actions of PI3K alpha, INPP4B, and PIKfyve, which contribute to autophagic degradation and protection against proteotoxic stress. These findings provide insights into the coordination of lysosome regeneration during autophagy.
Editorial Material
Cell Biology
Samuel J. Rodgers, Emily Jones, Christina A. Mitchell, Meagan J. McGrath
Summary: Macroautophagy/autophagy plays a crucial role in maintaining protein and organelle quality and protecting against aging and neurodegeneration. In nutrient-rich conditions, a sequential phosphoinositide conversion pathway enables lysosome repopulation to support basal autophagy.
Review
Cell Biology
Randini Nanayakkara, Rajendra Gurung, Samuel J. J. Rodgers, Matthew J. J. Eramo, Georg Ramm, Christina A. A. Mitchell, Meagan J. J. McGrath
Summary: This review provides an overview of the importance of lysosome reformation in maintaining autophagy function and the role of ALR dysfunction in various diseases.
Article
Oncology
Samuel J. Rodgers, Lisa M. Ooms, Christina A. Mitchell
Summary: Wnt/β-catenin signaling is hyperactivated in many human cancers, including 50% of breast cancers. Repurposing the FDA-approved drug pyrvinium, which suppresses Wnt signaling, may be a more efficient method to target this pathway. We demonstrate that breast cancer cells with high expression of the oncogene INPP4B are selectively sensitive to pyrvinium treatment, suggesting its potential as a therapeutic strategy for breast cancers with high INPP4B expression.
