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  1. Collection ; Online: Colloquium series on the building blocks of the cell

    Nabi, Ivan R.

    2013  

    Title variant Colloquium series on the building blocks of the cell: cell structure and function
    Subject code 571.6
    Language English
    Dates of publication Began with: Lecture #1 (2013).
    Publisher Morgan & Claypool Life Sciences
    Publishing place San Rafael, CA
    Document type Collection ; Online
    ZDB-ID 3165397-2
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  2. Article ; Online: Scaffolds and the scaffolding domain: an alternative paradigm for caveolin-1 signaling.

    Lim, John E / Bernatchez, Pascal / Nabi, Ivan R

    Biochemical Society transactions

    2024  

    Abstract: Caveolin-1 (Cav1) is a 22 kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. ... ...

    Abstract Caveolin-1 (Cav1) is a 22 kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. Scaffolds were originally described as SDS-resistant oligomers composed of 10-15 Cav1 monomers observable as 8S complexes by sucrose velocity gradient centrifugation. Recently, cryoelectron microscopy (cryoEM) and super-resolution microscopy have shown that 8S complexes are interlocking structures composed of 11 Cav1 monomers each, which further assemble modularly to form higher-order scaffolds and caveolae. In addition, Cav1 can act as a critical signaling regulator capable of direct interactions with multiple client proteins, in particular, the endothelial nitric oxide (NO) synthase (eNOS), a role believed by many to be attributable to the highly conserved and versatile scaffolding domain (CSD). However, as the CSD is a hydrophobic domain located by cryoEM to the periphery of the 8S complex, it is predicted to be enmeshed in membrane lipids. This has led some to challenge its ability to interact directly with client proteins and argue that it impacts signaling only indirectly via local alteration of membrane lipids. Here, based on recent advances in our understanding of higher-order Cav1 structure formation, we discuss how the Cav1 CSD may function through both lipid and protein interaction and propose an alternate view in which structural modifications to Cav1 oligomers may impact exposure of the CSD to cytoplasmic client proteins, such as eNOS.
    Language English
    Publishing date 2024-03-25
    Publishing country England
    Document type Journal Article
    ZDB-ID 184237-7
    ISSN 1470-8752 ; 0300-5127
    ISSN (online) 1470-8752
    ISSN 0300-5127
    DOI 10.1042/BST20231570
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Caveolin-1 promotes mitochondrial health and limits mitochondrial ROS through ROCK/AMPK regulation of basal mitophagic flux.

    Timmins, Logan R / Ortiz-Silva, Milene / Joshi, Bharat / Li, Y Lydia / Dickson, Fiona H / Wong, Timothy H / Vandevoorde, Kurt R / Nabi, Ivan R

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2023  Volume 38, Issue 1, Page(s) e23343

    Abstract: Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that ... ...

    Abstract Caveolin-1 (CAV1), the main structural component of caveolae, is phosphorylated at tyrosine-14 (pCAV1), regulates signal transduction, mechanotransduction, and mitochondrial function, and plays contrasting roles in cancer progression. We report that CRISPR/Cas9 knockout (KO) of CAV1 increases mitochondrial oxidative phosphorylation, increases mitochondrial potential, and reduces ROS in MDA-MB-231 triple-negative breast cancer cells. Supporting a role for pCAV1, these effects are reversed upon expression of CAV1 phosphomimetic CAV1 Y14D but not non-phosphorylatable CAV1 Y14F. pCAV1 is a known effector of Rho-associated kinase (ROCK) signaling and ROCK1/2 signaling mediates CAV1 promotion of increased mitochondrial potential and decreased ROS production in MDA-MB-231 cells. CAV1/ROCK control of mitochondrial potential and ROS is caveolae-independent as similar results were observed in PC3 prostate cancer cells lacking caveolae. Increased mitochondrial health and reduced ROS in CAV1 KO MDA-MB-231 cells were reversed by knockdown of the autophagy protein ATG5, mitophagy regulator PINK1 or the mitochondrial fission protein Drp1 and therefore due to mitophagy. Use of the mitoKeima mitophagy probe confirmed that CAV1 signaling through ROCK inhibited basal mitophagic flux. Activation of AMPK, a major mitochondrial homeostasis protein inhibited by ROCK, is inhibited by CAV1-ROCK signaling and mediates the increased mitochondrial potential, decreased ROS, and decreased basal mitophagy flux observed in wild-type MDA-MB-231 cells. CAV1 regulation of mitochondrial health and ROS in cancer cells therefore occurs via ROCK-dependent inhibition of AMPK. This study therefore links pCAV1 signaling activity at the plasma membrane with its regulation of mitochondrial activity and cancer cell metabolism through control of mitophagy.
    MeSH term(s) Male ; Humans ; Caveolin 1/genetics ; Caveolin 1/metabolism ; AMP-Activated Protein Kinases/genetics ; AMP-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Mechanotransduction, Cellular ; Mitochondria/metabolism ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Mitochondrial Proteins/metabolism ; rho-Associated Kinases/genetics ; rho-Associated Kinases/metabolism
    Chemical Substances Caveolin 1 ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Reactive Oxygen Species ; Mitochondrial Proteins ; ROCK1 protein, human (EC 2.7.11.1) ; rho-Associated Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2023-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202201872RR
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Book ; Online: AI-based analysis of super-resolution microscopy

    Nabi, Ivan R. / Cardoen, Ben / Khater, Ismail M. / Gao, Guang / Wong, Timothy H. / Hamarneh, Ghassan

    Biological discovery in the absence of ground truth

    2023  

    Abstract: The nanoscale resolution of super-resolution microscopy has now enabled the use of fluorescent based molecular localization tools to study whole cell structural biology. Machine learning based analysis of super-resolution data offers tremendous potential ...

    Abstract The nanoscale resolution of super-resolution microscopy has now enabled the use of fluorescent based molecular localization tools to study whole cell structural biology. Machine learning based analysis of super-resolution data offers tremendous potential for discovery of new biology, that by definition is not known and lacks ground truth. Herein, we describe the application of weakly supervised learning paradigms to super-resolution microscopy and its potential to enable the accelerated exploration of the molecular architecture of subcellular macromolecules and organelles.

    Comment: 14 pages, 3 figures
    Keywords Quantitative Biology - Subcellular Processes ; Computer Science - Artificial Intelligence ; Computer Science - Computer Vision and Pattern Recognition ; Computer Science - Machine Learning ; Physics - Biological Physics ; Quantitative Biology - Quantitative Methods
    Publishing date 2023-05-26
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Tyrosine phosphorylation of tumor cell caveolin-1: impact on cancer progression.

    Wong, Timothy H / Dickson, Fiona H / Timmins, Logan R / Nabi, Ivan R

    Cancer metastasis reviews

    2020  Volume 39, Issue 2, Page(s) 455–469

    Abstract: Caveolin-1 (CAV1) has long been implicated in cancer progression, and while widely accepted as an oncogenic protein, CAV1 also has tumor suppressor activity. CAV1 was first identified in an early study as the primary substrate of Src kinase, a potent ... ...

    Abstract Caveolin-1 (CAV1) has long been implicated in cancer progression, and while widely accepted as an oncogenic protein, CAV1 also has tumor suppressor activity. CAV1 was first identified in an early study as the primary substrate of Src kinase, a potent oncoprotein, where its phosphorylation correlated with cellular transformation. Indeed, CAV1 phosphorylation on tyrosine-14 (Y14; pCAV1) has been associated with several cancer-associated processes such as focal adhesion dynamics, tumor cell migration and invasion, growth suppression, cancer cell metabolism, and mechanical and oxidative stress. Despite this, a clear understanding of the role of Y14-phosphorylated pCAV1 in cancer progression has not been thoroughly established. Here, we provide an overview of the role of Src-dependent phosphorylation of tumor cell CAV1 in cancer progression, focusing on pCAV1 in tumor cell migration, focal adhesion signaling and metabolism, and in the cancer cell response to stress pathways characteristic of the tumor microenvironment. We also discuss a model for Y14 phosphorylation regulation of CAV1 effector protein interactions via the caveolin scaffolding domain.
    MeSH term(s) Animals ; Caveolin 1/metabolism ; Cell Movement/physiology ; Disease Progression ; Focal Adhesions/metabolism ; Humans ; Neoplasms/metabolism ; Neoplasms/pathology ; Phosphorylation ; Tyrosine/metabolism ; src-Family Kinases/metabolism
    Chemical Substances Caveolin 1 ; Tyrosine (42HK56048U) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2020-05-21
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 604857-2
    ISSN 1573-7233 ; 0167-7659
    ISSN (online) 1573-7233
    ISSN 0167-7659
    DOI 10.1007/s10555-020-09892-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Correction: Actin Cytoskeleton Regulation of Epithelial Mesenchymal Transition in Metastatic Cancer Cells.

    Shankar, Jay / Nabi, Ivan R

    PloS one

    2015  Volume 10, Issue 7, Page(s) e0132759

    Abstract: This corrects the article DOI: 10.1371/journal.pone.0119954.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.pone.0119954.].
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Published Erratum
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0132759
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Single molecule network analysis identifies structural changes to caveolae and scaffolds due to mutation of the caveolin-1 scaffolding domain.

    Wong, Timothy H / Khater, Ismail M / Joshi, Bharat / Shahsavari, Mona / Hamarneh, Ghassan / Nabi, Ivan R

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 7810

    Abstract: Caveolin-1 (CAV1), the caveolae coat protein, also associates with non-caveolar scaffold domains. Single molecule localization microscopy (SMLM) network analysis distinguishes caveolae and three scaffold domains, hemispherical S2 scaffolds and smaller ... ...

    Abstract Caveolin-1 (CAV1), the caveolae coat protein, also associates with non-caveolar scaffold domains. Single molecule localization microscopy (SMLM) network analysis distinguishes caveolae and three scaffold domains, hemispherical S2 scaffolds and smaller S1B and S1A scaffolds. The caveolin scaffolding domain (CSD) is a highly conserved hydrophobic region that mediates interaction of CAV1 with multiple effector molecules. F92A/V94A mutation disrupts CSD function, however the structural impact of CSD mutation on caveolae or scaffolds remains unknown. Here, SMLM network analysis quantitatively shows that expression of the CAV1 CSD F92A/V94A mutant in CRISPR/Cas CAV1 knockout MDA-MB-231 breast cancer cells reduces the size and volume and enhances the elongation of caveolae and scaffold domains, with more pronounced effects on S2 and S1B scaffolds. Convex hull analysis of the outer surface of the CAV1 point clouds confirms the size reduction of CSD mutant CAV1 blobs and shows that CSD mutation reduces volume variation amongst S2 and S1B CAV1 blobs at increasing shrink values, that may reflect retraction of the CAV1 N-terminus towards the membrane, potentially preventing accessibility of the CSD. Detection of point mutation-induced changes to CAV1 domains highlights the utility of SMLM network analysis for mesoscale structural analysis of oligomers in their native environment.
    MeSH term(s) Caveolin 1/chemistry ; Cell Line ; Humans ; Mutation ; Protein Conformation ; Protein Domains/genetics
    Chemical Substances CAV1 protein, human ; Caveolin 1
    Language English
    Publishing date 2021-04-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-86770-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Basal Gp78-dependent mitophagy promotes mitochondrial health and limits mitochondrial ROS.

    Alan, Parsa / Vandevoorde, Kurt R / Joshi, Bharat / Cardoen, Ben / Gao, Guang / Mohammadzadeh, Yahya / Hamarneh, Ghassan / Nabi, Ivan R

    Cellular and molecular life sciences : CMLS

    2022  Volume 79, Issue 11, Page(s) 565

    Abstract: Mitochondria are major sources of cytotoxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, that when uncontrolled contribute to cancer progression. Maintaining a finely tuned, healthy mitochondrial population is essential for ... ...

    Abstract Mitochondria are major sources of cytotoxic reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, that when uncontrolled contribute to cancer progression. Maintaining a finely tuned, healthy mitochondrial population is essential for cellular homeostasis and survival. Mitophagy, the selective elimination of mitochondria by autophagy, monitors and maintains mitochondrial health and integrity, eliminating damaged ROS-producing mitochondria. However, mechanisms underlying mitophagic control of mitochondrial homeostasis under basal conditions remain poorly understood. E3 ubiquitin ligase Gp78 is an endoplasmic reticulum membrane protein that induces mitochondrial fission and mitophagy of depolarized mitochondria. Here, we report that CRISPR/Cas9 knockout of Gp78 in HT-1080 fibrosarcoma cells increased mitochondrial volume, elevated ROS production and rendered cells resistant to carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitophagy. These effects were phenocopied by knockdown of the essential autophagy protein ATG5 in wild-type HT-1080 cells. Use of the mito-Keima mitophagy probe confirmed that Gp78 promoted both basal and damage-induced mitophagy. Application of a spot detection algorithm (SPECHT) to GFP-mRFP tandem fluorescent-tagged LC3 (tfLC3)-positive autophagosomes reported elevated autophagosomal maturation in wild-type HT-1080 cells relative to Gp78 knockout cells, predominantly in proximity to mitochondria. Mitophagy inhibition by either Gp78 knockout or ATG5 knockdown reduced mitochondrial potential and increased mitochondrial ROS. Live cell analysis of tfLC3 in HT-1080 cells showed the preferential association of autophagosomes with mitochondria of reduced potential. Xenograft tumors of HT-1080 knockout cells show increased labeling for mitochondria and the cell proliferation marker Ki67 and reduced labeling for the TUNEL cell death reporter. Basal Gp78-dependent mitophagic flux is, therefore, selectively associated with reduced potential mitochondria promoting maintenance of a healthy mitochondrial population, limiting ROS production and tumor cell proliferation.
    MeSH term(s) Humans ; Mitophagy ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Reactive Oxygen Species/metabolism ; Ki-67 Antigen/metabolism ; Superoxides/metabolism ; Hydrogen Peroxide/pharmacology ; Mitochondria/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Autophagy/genetics
    Chemical Substances Carbonyl Cyanide m-Chlorophenyl Hydrazone (555-60-2) ; Reactive Oxygen Species ; Ki-67 Antigen ; Superoxides (11062-77-4) ; Hydrogen Peroxide (BBX060AN9V) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2022-10-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-022-04585-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: DEEMD: Drug Efficacy Estimation Against SARS-CoV-2 Based on Cell Morphology With Deep Multiple Instance Learning.

    Saberian, M Sadegh / Moriarty, Kathleen P / Olmstead, Andrea D / Hallgrimson, Christian / Jean, Francois / Nabi, Ivan R / Libbrecht, Maxwell W / Hamarneh, Ghassan

    IEEE transactions on medical imaging

    2022  Volume 41, Issue 11, Page(s) 3128–3145

    Abstract: Drug repurposing can accelerate the identification of effective compounds for clinical use against SARS-CoV-2, with the advantage of pre-existing clinical safety data and an established supply chain. RNA viruses such as SARS-CoV-2 manipulate cellular ... ...

    Abstract Drug repurposing can accelerate the identification of effective compounds for clinical use against SARS-CoV-2, with the advantage of pre-existing clinical safety data and an established supply chain. RNA viruses such as SARS-CoV-2 manipulate cellular pathways and induce reorganization of subcellular structures to support their life cycle. These morphological changes can be quantified using bioimaging techniques. In this work, we developed DEEMD: a computational pipeline using deep neural network models within a multiple instance learning framework, to identify putative treatments effective against SARS-CoV-2 based on morphological analysis of the publicly available RxRx19a dataset. This dataset consists of fluorescence microscopy images of SARS-CoV-2 non-infected cells and infected cells, with and without drug treatment. DEEMD first extracts discriminative morphological features to generate cell morphological profiles from the non-infected and infected cells. These morphological profiles are then used in a statistical model to estimate the applied treatment efficacy on infected cells based on similarities to non-infected cells. DEEMD is capable of localizing infected cells via weak supervision without any expensive pixel-level annotations. DEEMD identifies known SARS-CoV-2 inhibitors, such as Remdesivir and Aloxistatin, supporting the validity of our approach. DEEMD can be explored for use on other emerging viruses and datasets to rapidly identify candidate antiviral treatments in the future. Our implementation is available online at https://www.github.com/Sadegh-Saberian/DEEMD.
    MeSH term(s) Humans ; SARS-CoV-2 ; COVID-19 ; Antiviral Agents/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/metabolism
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2022-10-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 622531-7
    ISSN 1558-254X ; 0278-0062
    ISSN (online) 1558-254X
    ISSN 0278-0062
    DOI 10.1109/TMI.2022.3178523
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Membrane contact site detection (MCS-DETECT) reveals dual control of rough mitochondria-ER contacts.

    Cardoen, Ben / Vandevoorde, Kurt R / Gao, Guang / Ortiz-Silva, Milene / Alan, Parsa / Liu, William / Tiliakou, Ellie / Vogl, A Wayne / Hamarneh, Ghassan / Nabi, Ivan R

    The Journal of cell biology

    2023  Volume 223, Issue 1

    Abstract: Identification and morphological analysis of mitochondria-ER contacts (MERCs) by fluorescent microscopy is limited by subpixel resolution interorganelle distances. Here, the membrane contact site (MCS) detection algorithm, MCS-DETECT, reconstructs ... ...

    Abstract Identification and morphological analysis of mitochondria-ER contacts (MERCs) by fluorescent microscopy is limited by subpixel resolution interorganelle distances. Here, the membrane contact site (MCS) detection algorithm, MCS-DETECT, reconstructs subpixel resolution MERCs from 3D super-resolution image volumes. MCS-DETECT shows that elongated ribosome-studded riboMERCs, present in HT-1080 but not COS-7 cells, are morphologically distinct from smaller smooth contacts and larger contacts induced by mitochondria-ER linker expression in COS-7 cells. RiboMERC formation is associated with increased mitochondrial potential, reduced in Gp78 knockout HT-1080 cells and induced by Gp78 ubiquitin ligase activity in COS-7 and HeLa cells. Knockdown of riboMERC tether RRBP1 eliminates riboMERCs in both wild-type and Gp78 knockout HT-1080 cells. By MCS-DETECT, Gp78-dependent riboMERCs present complex tubular shapes that intercalate between and contact multiple mitochondria. MCS-DETECT of 3D whole-cell super-resolution image volumes, therefore, identifies novel dual control of tubular riboMERCs, whose formation is dependent on RRBP1 and size modulated by Gp78 E3 ubiquitin ligase activity.
    MeSH term(s) Humans ; Endoplasmic Reticulum/metabolism ; HeLa Cells ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; COS Cells ; Animals ; Chlorocebus aethiops ; Ribosomes/metabolism
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2023-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218154-x
    ISSN 1540-8140 ; 0021-9525
    ISSN (online) 1540-8140
    ISSN 0021-9525
    DOI 10.1083/jcb.202206109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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