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Costin N Antonescu

Costin N Antonescu
Toronto Metropolitan University

PhD, University of Toronto

About

94
Publications
23,486
Reads
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2,222
Citations
Additional affiliations
January 2012 - present
Ryerson University
January 2012 - October 2015
Ryerson University
Position
  • Assistant Profeasor
January 2009 - December 2011
The Scripps Research Institute
Position
  • Postdoctorate
Education
September 2002 - September 2008
University of Toronto
Field of study
  • Biochemistry

Publications

Publications (94)
Article
The epidermal growth factor receptor (EGFR) triggers the activation of many intracellular signals that control cell proliferation, growth, survival, migration, and differentiation. Given its wide expression, EGFR has many functions in development and tissue homeostasis. Some of the cellular outcomes of EGFR signaling involve alterations of specific...
Preprint
Clathrin-mediated endocytosis (CME) controls the internalization and function of a wide range of cell surface proteins. CME occurs by the assembly of clathrin and many other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). These structures recruit specific membrane protein cargo destined for internalization and...
Preprint
The dynamics of living cells can be studied by live-cell fluorescence microscopy. However, this often requires the use of excessive light energy to obtain good signal-to-noise ratio, which can then photobleach the fluorochromes used, and more worrisome, lead to photo-toxicity. Thus, strategies that can reduce the amount and/or exposure to excitatio...
Preprint
The epidermal growth factor receptor (EGFR) controls many cellular functions. Upon binding its ligand, the receptor undergoes dimerization, phosphorylation, and activation of signals including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway. While some studies indicated that EGFR signaling may be controlled by signal enrichment within membrane...
Article
The epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology. EGF binding to EGFR elicits the membrane recruitment and activation of phosphatidylinositol-3-kinase, leading to Akt phosphorylation and activation. Concomitantly, EGFR is recruited to clathrin-coated pits (CCPs), eventually leading to receptor endocytosis....
Preprint
Full-text available
Ultrasound and microbubbles (USMB) is a promising strategy for cancer therapy. USMB can induce a variety of effects on cells including transient formation of plasma membrane pores (sonoporation) and enhanced endocytosis, which enhance drug delivery, and can also lead to enhanced cell death. However, the outcomes of USMB on cell physiology are heter...
Preprint
The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand bi...
Article
Full-text available
The COVID-19 pandemic has highlighted the urgent need for the identification of new antiviral drug therapies for a variety of diseases. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2, while other related human coronaviruses cause diseases ranging from severe respiratory infections to the common cold. We developed a computatio...
Article
Full-text available
Chronic pain has been widely recognized as a major public health problem that impacts multiple aspects of patient quality of life. Unfortunately, chronic pain is often resistant to conventional analgesics, which are further limited by their various side effects. New therapeutic strategies and targets are needed to better serve the millions of peopl...
Preprint
Full-text available
The COVID-19 pandemic has led to an urgent need for the identification of new antiviral drug therapies that can be rapidly deployed to treat patients with this disease. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant...
Article
Biological research and many cell-based therapies rely on the successful delivery of cargo materials into cells. Intracellular delivery in an in vitro setting refers to a variety of physical and biochemical techniques developed for conducting rapid and efficient transport of materials across the plasma membrane. Generally, the techniques that are t...
Article
Glycans on proteins and cell surfaces are useful biomarkers for determining functional interactions with glycan binding proteins, potential disease states, or indeed level of differentiation. The ability to rapidly and sensitively detect or tag specific glycans on proteins provides a diagnostic tool with wide application in chemical glycobiology. T...
Chapter
The dynamic phosphorylation of phosphatidylinositol produces seven distinct but interconvertible phosphatidylinositol phosphates (PIPs). Each PIP exhibits specific enrichment in a subset of membrane compartments as a result of dynamic phosphorylation and dephosphorylation by lipid kinases and phosphatases, and/or by vesicle-mediated transport. Seve...
Preprint
Full-text available
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the causative agent of COVID19 that has infected >76M people and caused >1.68M deaths. The SARS-CoV2 Spike glycoprotein is responsible for the attachment and infection of target cells. The viral Spike protein serves the basis for many putative therapeutic countermeasures including vacci...
Article
Full-text available
The RET receptor tyrosine kinase plays important roles in regulating cellular proliferation, migration, and survival in the normal development of neural crest derived tissues. However, aberrant activation of RET, through oncogenic mutations or overexpression, can contribute to tumourigenesis, regional invasion, and metastasis of several human cance...
Article
Full-text available
Antibody combinations targeting cell surface receptors are a new modality of cancer therapy. The trafficking and signalling mechanisms regulated by such therapeutics are not fully understood but could underlie differential tumour responses. We explored EGFR trafficking upon treatment with the antibody combination Sym004 which has shown promise clin...
Article
Full-text available
Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasoun...
Article
Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under v...
Article
Full-text available
The serine/threonine kinase Akt is a master regulator of many diverse cellular functions, including survival, growth, metabolism, migration, and differentiation. Receptor tyrosine kinases are critical regulators of Akt, as a result of activation of phosphatidylinositol-3-kinase (PI3K) signaling leading to Akt activation upon receptor stimulation. T...
Preprint
Full-text available
Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasoun...
Article
Full-text available
Glycogen synthase kinase 3β (GSK3β) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear transcription factors, suggesting the possibility that GSK3β function is controlled through its nuclear localization. Here, using ARPE-19 and...
Article
Full-text available
Legionella pneumophila (Lp) exhibits different morphologies with varying degrees of virulence. Despite their detection in environmental sources of outbreaks and in respiratory tract secretions and lung autopsies from patients, the filamentous morphotype of Lp remains poorly studied. We previously demonstrated that filamentous Lp invades lung epithe...
Preprint
Full-text available
Glycogen synthase kinase 3β (GSK3β) phosphorylates and regulates a wide range of substrates involved in diverse cellular functions. Some GSK3β substrates, such as c-myc and snail, are nuclear-resident transcription factors, suggesting possible control of GSK3β function by regulation of its nuclear localization. Inhibition of mechanistic target of r...
Article
Full-text available
Clathrin-mediated endocytosis is a major regulator of cell surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor (EGF) receptor (EGFR) signaling is regulated by its accumul...
Article
The epidermal growth factor (EGF) receptor (EGFR) is an important regulator of cell growth, proliferation, survival, migration, and metabolism. EGF binding to EGFR triggers the activation of the receptor’s intrinsic kinase activity, in turn eliciting the recruitment of many secondary signaling proteins and activation of downstream signals, such as...
Article
Full-text available
The RET receptor tyrosine kinase is implicated in normal development and cancer. RET is expressed as two isoforms, RET9 and RET51, with unique C-terminal tail sequences that recruit distinct protein complexes to mediate signals. Upon activation, RET isoforms are internalized with distinct kinetics, suggesting differences in regulation. Here, we dem...
Article
The axons of the DA and DB classes of motor neurons fail to reach the dorsal cord in the absence of the guidance cue UNC-6/Netrin or its receptor UNC-5 in C. elegans. However, the axonal processes usually exit their cell bodies in the ventral cord in the absence of both molecules. Strains lacking functional versions of UNC-6 or UNC-5 have a low lev...
Article
Full-text available
Background Ultrasound and microbubbles (USMB) have been shown to enhance the intracellular uptake of molecules, generally thought to occur as a result of sonoporation. The underlying mechanism associated with USMB-enhanced intracellular uptake such as membrane disruption and endocytosis may also be associated with USMB-induced release of cellular m...
Conference Paper
Full-text available
Ultrasound and microbubbletreatment (USMB) can enhance the intracellular uptake of molecules, which otherwise would be excluded from the cell, through USMB-mediated transient membrane disruption and through enhanced endocytosis. However, the effect of USMB on the outward movement of molecules from cells is not well understood. This study investigat...
Article
Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular signaling pathw...
Article
Full-text available
Phosphoinositides (PIPs) are key regulators of membrane traffic and signaling. The interconversion of PIPs by lipid kinases and phosphatases regulates their functionality. Phosphatidylinositol (PI) and PIPs have a unique enrichment of 1-stearoyl-2-arachidonyl acyl species; however, the regulation and function of this specific acyl profile remains p...
Article
Full-text available
Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB) is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation...
Data
Diagram depicting the timing of measurements of membrane traffic used in this study. Shown are diagrams of the timing of the experimental manipulations, starting with the USMB stimulation in each case. Top panel: For cell-surface TfR level measurement, USMB stimulation is followed by a 5 min incubation, followed by rapid washing and fixation. Middl...
Data
Quantification of cellular fluorescence intensity, used for measurement of cell surface TfR and LAMP1, Tfn uptake and FITC-dextran uptake. RPE cells were subjected to detection of cell surface TfR levels (top panels, as per Figs 1, 6 and 8) or uptake of A555-Tfn (bottom panels, as per Fig 2). Shown are representative fluorescence micrographs (left...
Data
Full image panels for TIRF-M images shown in Fig 3. To allow visualization of clathrin structures the images shown in Fig 3 are magnified insets of larger images. Shown in this figure are the full images obtained by TIRF-M corresponding to the magnified image insets (shown by the white boxes) shown in Fig 3. Scale = 20 μm. (PDF)
Article
Full-text available
Receptor tyrosine kinases, such as the epidermal growth factor (EGF) receptor (EGFR) and Met lead to activation of intracellular signals including Akt, a critical regulator of cell survival, metabolism and proliferation. Upon binding their respective ligands, each of these receptors is recruited into clathrin coated pits (CCPs) eventually leading t...
Article
Full-text available
Macrophages and dendritic cells exposed to lipopolysaccharides (LPS) convert their lysosomes from small punctate organelles into a network of tubules. Tubular lysosomes have been implicated in phagosome maturation, retention of fluid-phase and antigen presentation. There is a growing appreciation that lysosomes act as sensors of stress and the meta...
Article
Full-text available
Epidermal Growth Factor (EGF) binding to its receptor (EGFR) activates several signaling intermediates including Akt, leading to control of cell survival and metabolism. Concomitantly, ligand-bound EGFR is incorporated into clathrin-coated pits, membrane structures containing clathrin and other proteins, eventually leading to receptor internalizati...
Article
The RET receptor tyrosine kinase contributes to kidney and nervous system development, and is implicated in a number of human cancers. RET is expressed as two protein isoforms, RET9 and RET51, with distinct interactions and signaling properties that contribute to these processes. RET isoforms are internalized from the cell surface into endosomal co...
Article
Full-text available
Receptor tyrosine kinases (RTK) are an important family of growth factor and hormone receptors that regulate many aspects of cellular physiology. Ligand binding by RTKs at the plasma membrane elicits activation of many signaling intermediates. The spatial and temporal regulation of RTK signaling within cells is an important determinant of receptor...
Article
Full-text available
The cell surface proteome controls numerous cellular functions including cell migration and adhesion, intercellular communication and nutrient uptake. Cell surface proteins are controlled by acute changes in protein abundance at the plasma membrane through regulation of endocytosis and recycling (endomembrane traffic). Many cellular signals regulat...
Conference Paper
Epidermal growth factor (EGF) receptor (EGFR) controls many aspects of cell physiology via the activation of intracellular signaling pathways. Ligand-bound EGFR elicits phosphorylation of Gab1, which activates phosphatidylinositol-3-kinase (PI3K), which in turn leads to Akt phosphorylation and activation, controlling cell survival and metabolism. R...
Conference Paper
Clathrin-mediated endocytosis (CME) is the principal mechanism for internalization of diverse cell surface proteins (called cargo) from the cell surface, and thus is an important regulator of the surface proteome. CME initiates with the recruitment of clathrin, the adaptor protein AP-2, and many other proteins to cargo-enriched membrane invaginatio...
Article
Full-text available
The cellular uptake of many nutrients and micronutrients governs both their cellular availability and their systemic homeostasis. The cellular rate of nutrient or ion uptake (e.g., glucose, Fe(3+), K(+)) or efflux (e.g., Na(+)) is governed by a complement of membrane transporters and receptors that show dynamic localization at both the plasma membr...
Conference Paper
The many proteins at the cell surface (collectively, the cell surface proteome) control numerous cellular functions. The amount of each protein at the cell surface is dynamically controlled by endocytosis and recycling. AMP-activated protein kinase (AMPK) is an important metabolic regulator that responds to energetic stress, such as increased cellu...
Conference Paper
Phosphoinositides (PtdInsPs) are important signaling lipids that regulate many cellular processes, including membrane trafficking and cell proliferation. There are seven interconvertible species of PtdInsPs based on the inositol headgroup phosphorylation. However, there are additional molecular species of PtdInsPs that differ by their acyl chain ty...
Conference Paper
Aberrant activity of the receptor tyrosine kinase ErbB1, either by receptor overexpression, mutation, or increased abundance of activating ligand is seen in many tumors. ErbB1 is an important driver for the aggressive growth of cancerous cells. Upon activation by its ligand epidermal growth factor (EGF), ErbB1 initiates several signalling pathways...
Article
Numerous endocytic accessory proteins (EAPs) mediate assembly and maturation of clathrin-coated pits (CCPs) into cargo-containing vesicles. Analysis of EAP function through bulk measurement of cargo uptake has been hampered due to potential redundancy among EAPs and, as we show here, the plasticity and resilience of clathrin-mediated endocytosis (C...