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11. Regulation of microRNA expression by the adaptor protein GRB2

Author

Stainthorp, Amy K, Lin, Chi-Chuan, Wang, Dapeng, Medhi, Ragini, Ahmed, Zamal, Suen, Kin Man, Miska, Eric A, Whitehouse, Adrian, Ladbury, John E, and Apollo - University of Cambridge Repository

Subjects
MicroRNAs, Base Sequence, Argonaute Proteins, Gene Silencing, GRB2 Adaptor Protein
Abstract

Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.

Published
2023

13. Abstract 3488: Truncated FGFR2 - a clinically actionable oncogene in multiple cancers

Author

Zingg, Daniel Kaspar, primary, Bhin, Jinhyuk, additional, Yemelyanenko, Julia, additional, Kas, Sjors M., additional, Lutz, Catrin, additional, Lin, Chi-Chuan, additional, Klarenbeek, Sjoerd, additional, Lee, Jessica K., additional, Silverman, Ian M., additional, Annunziato, Stefano, additional, Ven, Marieke van de, additional, Ali, Siraj M., additional, Burn, Timothy C., additional, Ganesan, Shridar, additional, Wessels, Lodewyk F., additional, and Jonkers, Jos, additional

Published
2023
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24. A Secreted RNA Binding Protein Forms RNA-Stabilizing Granules in the Honeybee Royal Jelly

Author

Maori, Eyal, primary, Navarro, Isabela Cunha, additional, Boncristiani, Humberto, additional, Seilly, David J., additional, Rudolph, Konrad Ludwig Moritz, additional, Sapetschnig, Alexandra, additional, Lin, Chi-Chuan, additional, Ladbury, John Edward, additional, Evans, Jay Daniel, additional, Heeney, Jonathan Luke, additional, and Miska, Eric Alexander, additional

Published
2019
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25. From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor

Author

Turner, Lewis D., Trinh, Chi H., Hubball, Ryan A., Orritt, Kyle M., Lin, Chi-Chuan, Burns, Julie E., Knowles, Margaret A., and Fishwick, Colin W. G.

Abstract

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.

Published
2022
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27. Hornet sting induced systemic allergic reaction and large local reaction with bulle formation and rhabdomyolysis

Author

Lin, Chi-Chuan, Chang, Ming-Yang, and Lin, Ja-Lian

Subjects
Paper wasps, Bites and stings -- Care and treatment, Bites and stings -- Complications, Insect allergy -- Care and treatment, Environmental issues, Health, Pharmaceuticals and cosmetics industries
Abstract

A 41-yr-old, previously healthy male was stung once by a hornet. The patient had no history of allergy or hornet stings. Physical examination revealed swelling of the right side of his body with blister formation on the extremities. Rhabdomyolysis developed. Treatment included corticosteroids, antihistamines, and cyproheptadine. The patient was discharged without sequellae after being hospitalized for 7 days. Key Words: Hornet sting; Systemic reaction; Local reaction; Rhabdomyolysis., CASE REPORT A 41-yr-old male was stung once by a hornet. He was previously healthy, taking no medications, had no allergies, and had never been stung by a hornet or [...]

Published
2003

28. Corrigendum: Grb2 monomer–dimer equilibrium determines normal versus oncogenic function

Author

Ahmed, Zamal, Timsah, Zahra, Suen, Kin M., Cook, Nathan P., Lee IV, Gilbert R., Lin, Chi-Chuan, Gagea, Mihai, Marti, Angel A., and Ladbury, John E.

Subjects
Male, MAP Kinase Signaling System, Prostatic Neoplasms, Breast Neoplasms, Corrigenda, src Homology Domains, HEK293 Cells, Tissue Array Analysis, Son of Sevenless Proteins, Colonic Neoplasms, Humans, Tyrosine, Female, Phosphorylation, Protein Multimerization, GRB2 Adaptor Protein, Signal Transduction
Abstract

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression.

Published
2015

34. Inhibition of Basal FGF Receptor Signaling by Dimeric Grb2

Author

Lin, Chi-Chuan, primary, Melo, Fernando A., additional, Ghosh, Ragini, additional, Suen, Kin M., additional, Stagg, Loren J., additional, Kirkpatrick, John, additional, Arold, Stefan T., additional, Ahmed, Zamal, additional, and Ladbury, John E., additional

Published
2012
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36. Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity.

Author

Ahmed, Zamal, Lin, Chi-Chuan, Suen, Kin M., Melo, Fernando A., Levitt, James A., Suhling, Klaus, and Ladbury, John E.

Subjects
*PHOSPHORYLATION, *KINASES, *PHOSPHATASES, *ADAPTOR proteins, *FIBROBLAST growth factors
Abstract

Constitutive receptor tyrosine kinase phosphorylation requires regulation of kinase and phosphatase activity to prevent aberrant signal transduction. A dynamic mechanism is described here in which the adaptor protein, growth factor receptor-bound protein 2 (Grb2), controls fibroblast growth factor receptor 2 (FGFR2) signaling by regulating receptor kinase and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) phosphatase activity in the absence of extracellular stimulation. FGFR2 cycles between its kinase-active, partially phosphorylated, nonsignaling state and its Shp2-dephosphorylated state. Concurrently, Shp2 cycles between its FGFR2-phosphorylated and dephosphorylated forms. Both reciprocal activities of FGFR2 and Shp2 were inhibited by binding of Grb2 to the receptor. Phosphorylation of Grb2 by FGFR2 abrogated its binding to the receptor, resulting in up-regulation of both FGFR2's kinase and Shp2's phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2-Grb2 complex. This cycling of enzymatic activity results in a homeostatic, signaling-incompetent state. Growth factor binding perturbs this background cycling, promoting increased FGFR2 phosphorylation and kinase activity, Grb2 dissociation, and downstream signaling. Grb2 therefore exerts constitutive control over the mutually dependent activities of FGFR2 and Shp2. [ABSTRACT FROM AUTHOR]

Published
2013
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37. Grb2 binding induces phosphorylation-independent activation of Shp2

Author

Kin Man Suen, John E. Ladbury, Zamal Ahmed, Lukasz Wieteska, Chi-Chuan Lin, Arnout P. Kalverda, Lin, Chi-Chuan [0000-0003-3071-172X], Suen, Kin Man [0000-0001-9452-2528], Ahmed, Zamal [0000-0003-3400-6577], Ladbury, John E [0000-0002-6328-7200], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, QH301-705.5, Phosphatase, Medicine (miscellaneous), Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein tyrosine phosphatase, General Biochemistry, Genetics and Molecular Biology, Receptor tyrosine kinase, Article, 03 medical and health sciences, 0302 clinical medicine, Tyrosine, Biology (General), Phosphorylation, Protein kinase A, GRB2 Adaptor Protein, biology, Chemistry, fungi, Signal transducing adaptor protein, food and beverages, Growth factor signalling, Cell biology, Enzyme Activation, 030104 developmental biology, Enzyme mechanisms, biology.protein, GRB2, Signal transduction, biological phenomena, cell phenomena, and immunity, General Agricultural and Biological Sciences, 030217 neurology & neurosurgery, Signal Transduction
Abstract

The regulation of phosphatase activity is fundamental to the control of intracellular signalling and in particular the tyrosine kinase-mediated mitogen-activated protein kinase (MAPK) pathway. Shp2 is a ubiquitously expressed protein tyrosine phosphatase and its kinase-induced hyperactivity is associated with many cancer types. In non-stimulated cells we find that binding of the adaptor protein Grb2, in its monomeric state, initiates Shp2 activity independent of phosphatase phosphorylation. Grb2 forms a bidentate interaction with both the N-terminal SH2 and the catalytic domains of Shp2, releasing the phosphatase from its auto-inhibited conformation. Grb2 typically exists as a dimer in the cytoplasm. However, its monomeric state prevails under basal conditions when it is expressed at low concentration, or when it is constitutively phosphorylated on a specific tyrosine residue (Y160). Thus, Grb2 can activate Shp2 and downstream signal transduction, in the absence of extracellular growth factor stimulation or kinase-activating mutations, in response to defined cellular conditions. Therefore, direct binding of Grb2 activates Shp2 phosphatase in the absence of receptor tyrosine kinase up-regulation., Lin et al. investigate the interactions between adaptor protein, Grb2, and the ubiquitously expressed protein tyrosine phosphatase, Shp2. They find that monomeric Grb2 can activate Shp2 and its downstream signalling in the absence of up-regulation of receptor tyrosine kinases in response to different cellular conditions. They find that cancer-related signalling in breast cancer cells can be attributed to the binding of Grb2 to Shp2.

Published
2020

39. Expansion microscopy reveals subdomains in C. elegans germ granules.

Author

Suen KM, Sheard TM, Lin CC, Milonaityte D, Jayasinghe I, and Ladbury JE

Subjects
Animals, Germ Cell Ribonucleoprotein Granules, Microscopy, Organelles metabolism, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins genetics
Abstract

Light and electron microscopy techniques have been indispensable in the identification and characterization of liquid-liquid phase separation membraneless organelles. However, for complex membraneless organelles such as the perinuclear germ granule in C. elegans , our understanding of how the intact organelle is regulated is hampered by (1) technical limitations in confocal fluorescence imaging for the simultaneous examination of multiple granule protein markers and (2) inaccessibility of electron microscopy. We take advantage of the newly developed super resolution method of expansion microscopy (ExM) and in situ staining of the whole proteome to examine the C. elegans germ granule, the P granule. We show that in small RNA pathway mutants, the P granule is smaller compared with WT animals. Furthermore, we investigate the relationship between the P granule and two other germ granules, Mutator foci and Z granule, and show that they are located within the same protein-dense regions while occupying distinct subdomains within this ultrastructure. This study will serve as an important tool in our understanding of germ granule biology and the biological role of liquid-liquid phase separation., (© 2023 Suen et al.)

Published
2023
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40. Using the Superfolder GFP (sfGFP) System to Study Plant Peroxisomal Protein Import.

Author

Al-Hajaya Y, Lin CC, and Baker A

Subjects
Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Protein Transport, Plants, Genetically Modified metabolism, Protein Folding, Peroxisomes metabolism, Arabidopsis genetics, Arabidopsis metabolism
Abstract

The fusing of a protein of interest to a fluorescent protein followed by fluorescence microscopy is a very common method of determining protein localization and dynamics. However even small fluorescent proteins can be large enough to affect protein folding and localization, therefore the ability to use a smaller tag but still be able to detect a fluorescent signal in live cell imaging experiments is extremely valuable. The self-assembling split sfGFP OPT system allows the fusion of the protein of interest with the 11th β-strand of super-folder GFP (sfGFP11) which is only 13 amino acids long. When this construct is delivered into protoplasts made from transgenic plants expressing sfGFP1-10 (sfGFP1-10 OPT ) targeted to the desired compartment, the two parts assemble and fluorescence is reconstituted that can be detected by confocal laser scanning microscopy. Here, we present the application of this method for protein targeting to plant peroxisomes using Catalase (CAT2 of Arabidopsis thaliana) as an example. As peroxisomes are able to import folded and oligomeric proteins, careful consideration of appropriate controls is also required to ensure correct interpretation of the results., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2023
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