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Dive into the research topics where Lily S. Cheung is active.

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Featured researches published by Lily S. Cheung.


Annual Review of Biochemistry | 2015

Transport of Sugars

Li Qing Chen; Lily S. Cheung; Liang Feng; Widmar Tanner; Wolf B. Frommer

Soluble sugars serve five main purposes in multicellular organisms: as sources of carbon skeletons, osmolytes, signals, and transient energy storage and as transport molecules. Most sugars are derived from photosynthetic organisms, particularly plants. In multicellular organisms, some cells specialize in providing sugars to other cells (e.g., intestinal and liver cells in animals, photosynthetic cells in plants), whereas others depend completely on an external supply (e.g., brain cells, roots and seeds). This cellular exchange of sugars requires transport proteins to mediate uptake or release from cells or subcellular compartments. Thus, not surprisingly, sugar transport is critical for plants, animals, and humans. At present, three classes of eukaryotic sugar transporters have been characterized, namely the glucose transporters (GLUTs), sodium-glucose symporters (SGLTs), and SWEETs. This review presents the history and state of the art of sugar transporter research, covering genetics, biochemistry, and physiology-from their identification and characterization to their structure, function, and physiology. In humans, understanding sugar transport has therapeutic importance (e.g., addressing diabetes or limiting access of cancer cells to sugars), and in plants, these transporters are critical for crop yield and pathogen susceptibility.


Nature | 2015

Structure of a eukaryotic SWEET transporter in a homotrimeric complex.

Yuyong Tao; Lily S. Cheung; Shuo Li; Joon Seob Eom; Li Qing Chen; Yan Xu; Kay Perry; Wolf B. Frommer; Liang Feng

Eukaryotes rely on efficient distribution of energy and carbon skeletons between organs in the form of sugars. Glucose in animals and sucrose in plants serve as the dominant distribution forms. Cellular sugar uptake and release require vesicular and/or plasma membrane transport proteins. Humans and plants use proteins from three superfamilies for sugar translocation: the major facilitator superfamily (MFS), the sodium solute symporter family (SSF; only in the animal kingdom), and SWEETs. SWEETs carry mono- and disaccharides across vacuolar or plasma membranes. Plant SWEETs play key roles in sugar translocation between compartments, cells, and organs, notably in nectar secretion, phloem loading for long distance translocation, pollen nutrition, and seed filling. Plant SWEETs cause pathogen susceptibility possibly by sugar leakage from infected cells. The vacuolar Arabidopsis thaliana AtSWEET2 sequesters sugars in root vacuoles; loss-of-function mutants show increased susceptibility to Pythium infection. Here we show that its orthologue, the vacuolar glucose transporter OsSWEET2b from rice (Oryza sativa), consists of an asymmetrical pair of triple-helix bundles, connected by an inversion linker transmembrane helix (TM4) to create the translocation pathway. Structural and biochemical analyses show OsSWEET2b in an apparent inward (cytosolic) open state forming homomeric trimers. TM4 tightly interacts with the first triple-helix bundle within a protomer and mediates key contacts among protomers. Structure-guided mutagenesis of the close paralogue SWEET1 from Arabidopsis identified key residues in substrate translocation and protomer crosstalk. Insights into the structure–function relationship of SWEETs are valuable for understanding the transport mechanism of eukaryotic SWEETs and may be useful for engineering sugar flux.


Development | 2009

Feedback control of the EGFR signaling gradient: superposition of domain-splitting events in Drosophila oogenesis.

Jeremiah J. Zartman; Jitendra S. Kanodia; Lily S. Cheung; Stanislav Y. Shvartsman

The morphogenesis of structures with repeated functional units, such as body segments and appendages, depends on multi-domain patterns of cell signaling and gene expression. We demonstrate that during Drosophila oogenesis, the two-domain expression pattern of Broad, a transcription factor essential for the formation of the two respiratory eggshell appendages, is established by a single gradient of EGFR activation that induces both Broad and Pointed, which mediates repression of Broad. Two negative-feedback loops provided by the intracellular inhibitors of EGFR signaling, Kekkon-1 and Sprouty, control the number and position of Broad-expressing cells and in this way influence eggshell morphology. Later in oogenesis, the gradient of EGFR activation is split into two smaller domains in a process that depends on Argos, a secreted antagonist of EGFR signaling. In contrast to the previously proposed model of eggshell patterning, we show that the two-domain pattern of EGFR signaling is not essential for specifying the number of appendages. Thus, the processes that define the two-domain patterns of Broad and EGFR activation are distinct; their actions are separated in time and have different effects on eggshell morphology.


Proceedings of the National Academy of Sciences of the United States of America | 2012

Transcriptional interpretation of the EGF receptor signaling gradient

Alisa Fuchs; Lily S. Cheung; Enrica Charbonnier; Stanislav Y. Shvartsman; George Pyrowolakis

Epidermal growth factor receptor (EGFR) controls a wide range of developmental events, from body axes specification in insects to cardiac development in humans. During Drosophila oogenesis, a gradient of EGFR activation patterns the follicular epithelium. Multiple transcriptional targets of EGFR in this tissue have been identified, but their regulatory elements are essentially unknown. We report the regulatory elements of broad (br) and pipe (pip), two important targets of EGFR signaling in Drosophila oogenesis. br is expressed in a complex pattern that prefigures the formation of respiratory eggshell appendages. We found that this pattern is generated by dynamic activities of two regulatory elements, which display different responses to Pointed, Capicua, and Mirror, transcription factors involved in the EGFR-mediated gene expression. One of these elements is active in a pattern similar to pip, a gene repressed by EGFR and essential for establishing the dorsoventral polarity of the embryo. We demonstrate that this similarity of expression depends on a common sequence motif that binds Mirror in vitro and is essential for transcriptional repression in vivo.


Current Opinion in Genetics & Development | 2011

Pattern formation by receptor tyrosine kinases: analysis of the Gurken gradient in Drosophila oogenesis

Lily S. Cheung; Trudi Schüpbach; Stanislav Y. Shvartsman

Spatial patterns of cell differentiation in developing tissues can be controlled by receptor tyrosine kinase (RTK) signaling gradients, which may form when locally secreted ligands activate uniformly expressed receptors. Graded activation of RTKs can span multiple cell diameters, giving rise to spatiotemporal patterns of signaling through the Extracellular Signal Regulated/Mitogen Activated Protein Kinase (ERK/MAPK), which connects receptor activation to multiple aspects of tissue morphogenesis. This general mechanism has been identified in numerous developmental contexts, from body axis specification in insects to patterning of the mammalian neocortex. We review recent quantitative studies of this mechanism in Drosophila oogenesis, an established genetic model of signaling through the Epidermal Growth Factor Receptor (EGFR), a highly conserved RTK.


Physical Biology | 2011

Pattern formation by a moving morphogen source.

Jeremiah J. Zartman; Lily S. Cheung; Matthew G. Niepielko; Christine Bonini; Benjamin Haley; Nir Yakoby; Stanislav Y. Shvartsman

During Drosophila melanogaster oogenesis, the follicular epithelium that envelops the germline cyst gives rise to an elaborate eggshell, which houses the future embryo and mediates its interaction with the environment. A prominent feature of the eggshell is a pair of dorsal appendages, which are needed for embryo respiration. Morphogenesis of this structure depends on broad, a zinc-finger transcription factor, regulated by the EGFR pathway. While much has been learned about the mechanisms of broad regulation by EGFR, current understanding of processes that shape the spatial pattern of broad expression is incomplete. We propose that this pattern is defined by two different phases of EGFR activation: an early, posterior-to-anterior gradient of EGFR signaling sets the posterior boundary of broad expression, while the anterior boundary is set by a later phase of EGFR signaling, distributed in a dorsoventral gradient. This model can explain the wild-type pattern of broad in D. melanogaster, predicts how this pattern responds to genetic perturbations, and provides insight into the mechanisms driving diversification of eggshell patterning. The proposed model of the broad expression pattern can be used as a starting point for the quantitative analysis of a large number of gene expression patterns in Drosophila oogenesis.


Development | 2012

EGFR-dependent network interactions that pattern Drosophila eggshell appendages

David S. A. Simakov; Lily S. Cheung; L. M. Pismen; Stanislav Y. Shvartsman

Similar to other organisms, Drosophila uses its Epidermal Growth Factor Receptor (EGFR) multiple times throughout development. One crucial EGFR-dependent event is patterning of the follicular epithelium during oogenesis. In addition to providing inductive cues necessary for body axes specification, patterning of the follicle cells initiates the formation of two respiratory eggshell appendages. Each appendage is derived from a primordium comprising a patch of cells expressing broad (br) and an adjacent stripe of cells expressing rhomboid (rho). Several mechanisms of eggshell patterning have been proposed in the past, but none of them can explain the highly coordinated expression of br and rho. To address some of the outstanding issues in this system, we synthesized the existing information into a revised mathematical model of follicle cell patterning. Based on the computational model analysis, we propose that dorsal appendage primordia are established by sequential action of feed-forward loops and juxtacrine signals activated by the gradient of EGFR signaling. The model describes pattern formation in a large number of mutants and points to several unanswered questions related to the dynamic interaction of the EGFR and Notch pathways.


Proceedings of the National Academy of Sciences of the United States of America | 2013

Dynamic model for the coordination of two enhancers of broad by EGFR signaling

Lily S. Cheung; David S. A. Simakov; Alisa Fuchs; George Pyrowolakis; Stanislav Y. Shvartsman

Significance Temporal regulation of a typical developmental control gene depends on multiple enhancers, which makes it important to understand how enhancers coordinate their activities in time. We describe a mechanism for such coordination in Drosophila oogenesis, where the expression of the transcription factor Broad depends on sequential activities of two enhancers. The early enhancer is essential for activity of the late one. To explain this requirement, we propose a mechanism based on a network with feedforward and feedback loops. This network interprets and modulates the epidermal growth factor receptor (EGFR) signaling gradient that controls both enhancers. Experiments and computational modeling show that understanding Broad expression is impossible without simultaneously considering two enhancers, a dynamic gradient, and a network with extracellular and intracellular components. Although it is widely appreciated that a typical developmental control gene is regulated by multiple enhancers, coordination of enhancer activities remains poorly understood. We propose a mechanism for such coordination in Drosophila oogenesis, when the expression of the transcription factor Broad (BR) evolves from a uniform to a two-domain pattern that prefigures the formation of two respiratory eggshell appendages. This change reflects sequential activities of two enhancers of the br gene, early and late, both of which are controlled by the epidermal growth factor receptor (EGFR) pathway. The late enhancer controls br in the appendage-producing cells, but the function of the early enhancer remained unclear. We found that the early enhancer is essential for the activity of the late enhancer and induction of eggshell appendages. This requirement can be explained by a mechanism whereby the BR protein produced by the early enhancer protects the late enhancer from EGFR-dependent repression. We illustrate this complex mechanism using a computational model that correctly predicts the wild-type dynamics of BR expression and its response to genetic perturbations.


Developmental Biology | 2015

BMP-dependent gene repression cascade in Drosophila eggshell patterning

Enrica Charbonnier; Alisa Fuchs; Lily S. Cheung; Mrinal Chayengia; Ville Veikkolainen; Janine Seyfferth; Stanislav Y. Shvartsman; George Pyrowolakis

Bone Morphogenetic Proteins (BMPs) signal by activating Smad transcription factors to control a number of decisions during animal development. In Drosophila, signaling by the BMP ligand Decapentaplegic (Dpp) involves the activity of brinker (brk) which, in most contexts, is repressed by Dpp. Brk encodes a transcription factor which represses BMP signaling output by antagonizing Smad-dependent target gene activation. Here, we study BMP-dependent gene regulation during Drosophila oogenesis by following the signal transmission from Dpp to its target broad (br), a gene with a crucial function in eggshell patterning. We identify regulatory sequences that account for expression of both brk and br, and connect these to the transcription factors of the pathway. We show that Dpp directly regulates brk transcription through Smad- and Schnurri (Shn)-dependent repression. Brk is epistatic to Dpp in br expression and activates br indirectly, through removal of a repressor, which is yet to be identified. Our work provides first cis-regulatory insights into transcriptional interpretation of BMP signaling in eggshell morphogenesis and defines a transcriptional cascade that connects Dpp to target gene regulation.


Methods of Molecular Biology | 2015

A Multiplex Fluorescent In Situ Hybridization Protocol for Clonal Analysis of Drosophila Oogenesis

Lily S. Cheung; Stanislav Y. Shvartsman

Fluorescent in situ hybridization (FISH) is a common inmunohistochemical method used to examine the distribution of RNAs in tissue samples. In mosaic tissues composed of a mixed population of wild-type and loss-of- or gain-of-function mutant cells, FISH allows comparison of the effect of the perturbation on gene expression patterns in a mutant cell and its wild-type neighbors. Here, we provide a protocol for the detection of RNA in Drosophila mosaic follicular epithelia, where the mosaic analysis with a repressible cell marker (MARCM) technique is used for expression of transgenes.

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Wolf B. Frommer

Carnegie Institution for Science

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Alisa Fuchs

University of Freiburg

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Li Qing Chen

Carnegie Institution for Science

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Kay Perry

Argonne National Laboratory

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Yan Xu

Stanford University

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