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3. An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.

Author

Nguyen, My, Moiani, Davide, Ahmed, Zamal, Arvai, Andrew, Namjoshi, Sarita, Shin, Dave, Fedorov, Yuriy, Selvik, Edward, Jones, Darin, Pink, John, Yan, Yan, Laverty, Daniel, Nagel, Zachary, Tainer, John, and Gerson, Stanton

Subjects
Cancer, DNA repair, Ligand, Structures, UDG, Catalytic Domain, Cytidine Deaminase, DNA Damage, DNA Repair, Humans, Minor Histocompatibility Antigens, Uracil, Uracil-DNA Glycosidase
Abstract

Human uracil DNA-glycosylase (UDG) is the prototypic and first identified DNA glycosylase with a vital role in removing deaminated cytosine and incorporated uracil and 5-fluorouracil (5-FU) from DNA. UDG depletion sensitizes cells to high APOBEC3B deaminase and to pemetrexed (PEM) and floxuridine (5-FdU), which are toxic to tumor cells through incorporation of uracil and 5-FU into DNA. To identify small-molecule UDG inhibitors for pre-clinical evaluation, we optimized biochemical screening of a selected diversity collection of >3,000 small-molecules. We found aurintricarboxylic acid (ATA) as an inhibitor of purified UDG at an initial calculated IC50

Published
2021

4. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors

Author

Brosey, Chris A, Houl, Jerry H, Katsonis, Panagiotis, Balapiti-Modarage, Lakshitha PF, Bommagani, Shobanbabu, Arvai, Andy, Moiani, Davide, Bacolla, Albino, Link, Todd, Warden, Leslie S, Lichtarge, Olivier, Jones, Darin E, Ahmed, Zamal, and Tainer, John A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Coronaviruses, Emerging Infectious Diseases, Infectious Diseases, Biodefense, 5.1 Pharmaceuticals, Generic health relevance, Infection, Good Health and Well Being, Amino Acid Sequence, Antiviral Agents, Catalytic Domain, Coronavirus Papain-Like Proteases, Crystallography, X-Ray, Drug Discovery, Enzyme Inhibitors, Glycoside Hydrolases, Humans, Models, Molecular, Protein Domains, SARS-CoV-2, Small Molecule Libraries, Structure-Activity Relationship, Xanthines, COVID-19 Drug Treatment, SARS-CoV-2 Nsp3 macrodomain, Poly(ADP-Ribose) glycohydrolase, PARG inhibitor, Evolutionary trace, In silico screening, Drug discovery, Biophysics, Biochemistry and cell biology
Abstract

Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.

Published
2021

5. Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin.

Author

Bacolla, Albino, Sengupta, Shiladitya, Ye, Zu, Yang, Chunying, Mitra, Joy, De-Paula, Ruth, Hegde, Muralidhar, Ahmed, Zamal, Mort, Matthew, Cooper, David, Mitra, Sankar, and Tainer, John

Subjects
Acetylation, Animals, Cell Line, Tumor, Cell Nucleus, Chromatin, DNA Glycosylases, DNA Repair, Datasets as Topic, Evolution, Molecular, Genes, Helminth, Genes, Homeobox, HEK293 Cells, Helminth Proteins, Humans, Invertebrates, Lysine, Mutation, Neoplasm Proteins, Neoplasms, Oxidation-Reduction, Protein Processing, Post-Translational, Proteome, Sequence Alignment, Sequence Homology, Amino Acid, Transcription Initiation Site, Vertebrates
Abstract

Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen.

Published
2021

9. An efficient chemical screening method for structure-based inhibitors to nucleic acid enzymes targeting the DNA repair-replication interface and SARS CoV-2

Author

Moiani, Davide, primary, Link, Todd M., additional, Brosey, Chris A., additional, Katsonis, Panagiotis, additional, Lichtarge, Olivier, additional, Kim, Youngchang, additional, Joachimiak, Andrzej, additional, Ma, Zhijun, additional, Kim, In-Kwon, additional, Ahmed, Zamal, additional, Jones, Darin E., additional, Tsutakawa, Susan E., additional, and Tainer, John A., additional

Published
2021
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11. An efficient chemical screening method for structure-based inhibitors to nucleic acid enzymes targeting the DNA repair-replication interface and SARS CoV-2

Author

Moiani, Davide, Link, Todd M, Brosey, Chris A, Katsonis, Panagiotis, Lichtarge, Olivier, Kim, Youngchang, Joachimiak, Andrzej, Ma, Zhijun, Kim, In-Kwon, Ahmed, Zamal, Jones, Darin E, Tsutakawa, Susan E, and Tainer, John A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Prevention, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Cancer, COVID-19, DNA Repair, Humans, Molecular Docking Simulation, Nucleic Acids, SARS-CoV-2, Severe Acute Respiratory Syndrome, Chemical library, DNA replication and repair, Drug discovery, Sars-COV2, Biochemistry & Molecular Biology, Biochemistry and cell biology
Abstract

We present a Chemistry and Structure Screen Integrated Efficiently (CASSIE) approach (named for Greek prophet Cassandra) to design inhibitors for cancer biology and pathogenesis. CASSIE provides an effective path to target master keys to control the repair-replication interface for cancer cells and SARS CoV-2 pathogenesis as exemplified here by specific targeting of Poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose glycohydrolase ARH3 macrodomains plus SARS CoV-2 nonstructural protein 3 (Nsp3) Macrodomain 1 (Mac1) and Nsp15 nuclease. As opposed to the classical massive effort employing libraries with large numbers of compounds against single proteins, we make inhibitor design for multiple targets efficient. Our compact, chemically diverse, 5000 compound Goldilocks (GL) library has an intermediate number of compounds sized between fragments and drugs with predicted favorable ADME (absorption, distribution, metabolism, and excretion) and toxicological profiles. Amalgamating our core GL library with an approved drug (AD) library, we employ a combined GLAD library virtual screen, enabling an effective and efficient design cycle of ranked computer docking, top hit biophysical and cell validations, and defined bound structures using human proteins or their avatars. As new drug design is increasingly pathway directed as well as molecular and mechanism based, our CASSIE approach facilitates testing multiple related targets by efficiently turning a set of interacting drug discovery problems into a tractable medicinal chemistry engineering problem of optimizing affinity and ADME properties based upon early co-crystal structures. Optimization efforts are made efficient by a computationally-focused iterative chemistry and structure screen. Thus, we herein describe and apply CASSIE to define prototypic, specific inhibitors for PARG vs distinct inhibitors for the related macrodomains of ARH3 and SARS CoV-2 Nsp3 plus the SARS CoV-2 Nsp15 RNA nuclease.

Published
2021

13. Data from Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1

Author

Yuan, Xiangliang, primary, Duan, Yimin, primary, Xiao, Yi, primary, Sun, Kai, primary, Qi, Yutao, primary, Zhang, Yuan, primary, Ahmed, Zamal, primary, Moiani, Davide, primary, Yao, Jun, primary, Li, Hongzhong, primary, Zhang, Lin, primary, Yuzhalin, Arseniy E., primary, Li, Ping, primary, Zhang, Chenyu, primary, Badu-Nkansah, Akosua, primary, Saito, Yohei, primary, Liu, Xianghua, primary, Kuo, Wen-Ling, primary, Ying, Haoqiang, primary, Sun, Shao-Cong, primary, Chang, Jenny C., primary, Tainer, John A., primary, and Yu, Dihua, primary

Published
2023
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14. Supplementary Data from Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1

Author

Yuan, Xiangliang, primary, Duan, Yimin, primary, Xiao, Yi, primary, Sun, Kai, primary, Qi, Yutao, primary, Zhang, Yuan, primary, Ahmed, Zamal, primary, Moiani, Davide, primary, Yao, Jun, primary, Li, Hongzhong, primary, Zhang, Lin, primary, Yuzhalin, Arseniy E., primary, Li, Ping, primary, Zhang, Chenyu, primary, Badu-Nkansah, Akosua, primary, Saito, Yohei, primary, Liu, Xianghua, primary, Kuo, Wen-Ling, primary, Ying, Haoqiang, primary, Sun, Shao-Cong, primary, Chang, Jenny C., primary, Tainer, John A., primary, and Yu, Dihua, primary

Published
2023
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15. Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Author

Houl, Jerry H., Ye, Zu, Brosey, Chris A., Balapiti-Modarage, Lakshitha P. F., Namjoshi, Sarita, Bacolla, Albino, Laverty, Daniel, Walker, Brian L., Pourfarjam, Yasin, Warden, Leslie S., Babu Chinnam, Naga, Moiani, Davide, Stegeman, Roderick A., Chen, Mei-Kuang, Hung, Mien-Chie, Nagel, Zachary D., Ellenberger, Tom, Kim, In-Kwon, Jones, Darin E., Ahmed, Zamal, and Tainer, John A.

Published
2019
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17. 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

18. Data from An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors

Author

Indarte, Martin, primary, Puentes, Roisin, primary, Maruggi, Marco, primary, Ihle, Nathan T., primary, Grandjean, Geoffrey, primary, Scott, Michael, primary, Ahmed, Zamal, primary, Meuillet, Emmanuelle J., primary, Zhang, Shuxing, primary, Lemos, Robert, primary, Du-Cuny, Lei, primary, Layng, Fabiana I.A.L., primary, Correa, Ricardo G., primary, Bankston, Laurie A., primary, Liddington, Robert C., primary, Kirkpatrick, Lynn, primary, and Powis, Garth, primary

Published
2023
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19. Supplemental Information from An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors

Author

Indarte, Martin, primary, Puentes, Roisin, primary, Maruggi, Marco, primary, Ihle, Nathan T., primary, Grandjean, Geoffrey, primary, Scott, Michael, primary, Ahmed, Zamal, primary, Meuillet, Emmanuelle J., primary, Zhang, Shuxing, primary, Lemos, Robert, primary, Du-Cuny, Lei, primary, Layng, Fabiana I.A.L., primary, Correa, Ricardo G., primary, Bankston, Laurie A., primary, Liddington, Robert C., primary, Kirkpatrick, Lynn, primary, and Powis, Garth, primary

Published
2023
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20. Epigenetic–Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer

Author

Das, Chandrima, primary, Adhikari, Swagata, additional, Bhattacharya, Apoorva, additional, Chakraborty, Sanjukta, additional, Mondal, Payel, additional, Yadav, Shalini S., additional, Adhikary, Santanu, additional, Hunt, Clayton R., additional, Yadav, Kamlesh K., additional, Pandita, Shruti, additional, Roy, Siddhartha, additional, Tainer, John A., additional, Ahmed, Zamal, additional, and Pandita, Tej K., additional

Published
2023
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22. Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1

Author

Yuan, Xiangliang, primary, Duan, Yimin, additional, Xiao, Yi, additional, Sun, Kai, additional, Qi, Yutao, additional, Zhang, Yuan, additional, Ahmed, Zamal, additional, Moiani, Davide, additional, Yao, Jun, additional, Li, Hongzhong, additional, Zhang, Lin, additional, Yuzhalin, Arseniy E., additional, Li, Ping, additional, Zhang, Chenyu, additional, Badu-Nkansah, Akosua, additional, Saito, Yohei, additional, Liu, Xianghua, additional, Kuo, Wen-Ling, additional, Ying, Haoqiang, additional, Sun, Shao-Cong, additional, Chang, Jenny C., additional, Tainer, John A., additional, and Yu, Dihua, additional

Published
2022
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23. PLEKHA7 signaling is necessary for the growth of mutant KRAS driven colorectal cancer

Author

Jeung, Hei-Cheul, primary, Puentes, Roisin, additional, Aleshin, Alexander, additional, Indarte, Martin, additional, Correa, Ricardo G., additional, Bankston, Laurie A., additional, Layng, Fabiana I.A.L., additional, Ahmed, Zamal, additional, Wistuba, Ignacio, additional, Yao, Yong, additional, Duenas, Daniela G., additional, Zhang, Shuxing, additional, Meuillet, Emmanuelle J., additional, Marassi, Francesca, additional, Liddington, Robert C., additional, Kirkpatrick, Lynn, additional, and Powis, Garth, additional

Published
2021
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24. GRB2 enforces homology-directed repair initiation by MRE11

Author

Ye, Zu, primary, Xu, Shengfeng, additional, Shi, Yin, additional, Bacolla, Albino, additional, Syed, Aleem, additional, Moiani, Davide, additional, Tsai, Chi-Lin, additional, Shen, Qiang, additional, Peng, Guang, additional, Leonard, Paul G., additional, Jones, Darin E., additional, Wang, Bin, additional, Tainer, John A., additional, and Ahmed, Zamal, additional

Published
2021
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25. An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation

Author

Nguyen, My T., primary, Moiani, Davide, additional, Ahmed, Zamal, additional, Arvai, Andrew S., additional, Namjoshi, Sarita, additional, Shin, Dave S., additional, Fedorov, Yuriy, additional, Selvik, Edward J., additional, Jones, Darin E., additional, Pink, John, additional, Yan, Yan, additional, Laverty, Daniel J., additional, Nagel, Zachary D., additional, Tainer, John A., additional, and Gerson, Stanton L., additional

Published
2021
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26. Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors

Author

Brosey, Chris A., primary, Houl, Jerry H., additional, Katsonis, Panagiotis, additional, Balapiti-Modarage, Lakshitha P.F., additional, Bommagani, Shobanbabu, additional, Arvai, Andy, additional, Moiani, Davide, additional, Bacolla, Albino, additional, Link, Todd, additional, Warden, Leslie S., additional, Lichtarge, Olivier, additional, Jones, Darin E., additional, Ahmed, Zamal, additional, and Tainer, John A., additional

Published
2021
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27. Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

Author

Bacolla, Albino, primary, Sengupta, Shiladitya, additional, Ye, Zu, additional, Yang, Chunying, additional, Mitra, Joy, additional, De-Paula, Ruth B, additional, Hegde, Muralidhar L, additional, Ahmed, Zamal, additional, Mort, Matthew, additional, Cooper, David N, additional, Mitra, Sankar, additional, and Tainer, John A, additional

Published
2020
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31. Correction: An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors

Author

Indarte, Martin, primary, Puentes, Roisin, additional, Maruggi, Marco, additional, Ihle, Nathan T., additional, Grandjean, Geoffrey, additional, Scott, Michael, additional, Ahmed, Zamal, additional, Meuillet, Emmanuelle J., additional, Zhang, Shuxing, additional, Lemos, Robert, additional, Du-Cuny, Lei, additional, Layng, Fabiana I.A.L., additional, Correa, Ricardo G., additional, Bankston, Laurie A., additional, Liddington, Robert C., additional, Kirkpatrick, Lynn, additional, and Powis, Garth, additional

Published
2019
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33. An Inhibitor of the Pleckstrin Homology Domain of CNK1 Selectively Blocks the Growth of Mutant KRAS Cells and Tumors

Author

Indarte, Martin, primary, Puentes, Roisin, additional, Maruggi, Marco, additional, Ihle, Nathan T., additional, Grandjean, Geoffrey, additional, Scott, Michael, additional, Ahmed, Zamal, additional, Meuillet, Emmanuelle J., additional, Zhang, Shuxing, additional, Lemos, Robert, additional, Du-Cuny, Lei, additional, Layng, Fabiana I.A.L., additional, Correa, Ricardo G., additional, Bankston, Laurie A., additional, Liddington, Robert C., additional, Kirkpatrick, Lynn, additional, and Powis, Garth, additional

Published
2019
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35. 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

36. FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia.

Author

Akira Honda, Tomoko Kita, Seshadri, Shri Vidhya, Kazuyo Misaki, Ahmed, Zamal, Ladbury, John E., Richardson, Guy P., Shigenobu Yonemura, and Ladher, Raj K.

Subjects
HAIR cells, FIBROBLAST growth factor receptors, CADHERINS, PROTEIN transport, MECHANORECEPTORS, INNER ear physiology, CLATHRIN, PHOSPHORYLATION
Abstract

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity. [ABSTRACT FROM AUTHOR]

Published
2018
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39. A Novel Dual Kinase Function of the RET Proto-oncogene Negatively Regulates Activating Transcription Factor 4-mediated Apoptosis

Author

Bagheri-Yarmand, Rozita, primary, Sinha, Krishna M., additional, Gururaj, Anupama E., additional, Ahmed, Zamal, additional, Rizvi, Yasmeen Q., additional, Huang, Su-Chen, additional, Ladbury, John E., additional, Bogler, Oliver, additional, Williams, Michelle D., additional, Cote, Gilbert J., additional, and Gagel, Robert F., additional

Published
2015
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40. Identification of APS as a Novel Insulin Receptor Adapter Protein and Substrate

Author

PILLAY, TAHIR S., KOTANI, KEI, and AHMED, ZAMAL

Subjects
Diabetes -- Research, Health
Abstract

The Adapter Protein and Substrate (APS) is the newest member of a distinct and growing family of tyrosine kinase substrates including SH2-B[Alpha]/[Beta] and Lnk. These contain proline-rich regions, a pleckstrin [...]

Published
1999

47. 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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