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27 results on '"Coyle, Scott M."'

3. Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors

Author

Morsut, Leonardo, Roybal, Kole T, Xiong, Xin, Gordley, Russell M, Coyle, Scott M, Thomson, Matthew, and Lim, Wendell A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Bioengineering, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Cell Engineering, Cell Line, Dogs, Humans, Mice, Neurons, Receptors, Notch, Signal Transduction, Synthetic Biology, Transcription, Genetic, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The Notch protein is one of the most mechanistically direct transmembrane receptors-the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types. Because individual synNotch pathways do not share common signaling intermediates, the pathways are functionally orthogonal. Thus, multiple synNotch receptors can be used in the same cell to achieve combinatorial integration of environmental cues, including Boolean response programs, multi-cellular signaling cascades, and self-organized cellular patterns. SynNotch receptors provide extraordinary flexibility in engineering cells with customized sensing/response behaviors to user-specified extracellular cues.

Published
2016

4. Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution.

Author

Coyle, Scott M and Lim, Wendell A

Subjects
Humans, ras Guanine Nucleotide Exchange Factors, Signal Transduction, Feedback, Physiological, Protein Interaction Maps, e. coli, biochemistry, cell signaling, computational biology, dynamics, human, ras, reconstitution, systems biology, e. coli, Feedback, Physiological, Biochemistry and Cell Biology
Abstract

The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes (GEF/GAP) regulate Ras's ability to recruit multiple competing downstream effectors. We developed a multiplexed, multi-turnover assay for measuring the dynamic signaling behavior of in vitro reconstituted H-Ras signaling systems. By including both upstream regulators and downstream effectors, we can systematically map how different network configurations shape the dynamic system response. The concentration and identity of both upstream and downstream signaling components strongly impacted the timing, duration, shape, and amplitude of effector outputs. The distorted output of oncogenic alleles of Ras was highly dependent on the balance of positive (GAP) and negative (GEF) regulators in the system. We found that different effectors interpreted the same inputs with distinct output dynamics, enabling a Ras system to encode multiple unique temporal outputs in response to a single input. We also found that different Ras-to-GEF positive feedback mechanisms could reshape output dynamics in distinct ways, such as signal amplification or overshoot minimization. Mapping of the space of output behaviors accessible to Ras provides a design manual for programming Ras circuits, and reveals how these systems are readily adapted to produce an array of dynamic signaling behaviors. Nonetheless, this versatility comes with a trade-off of fragility, as there exist numerous paths to altered signaling behaviors that could cause disease.

Published
2016

6. Exploitation of Latent Allostery Enables the Evolution of New Modes of MAP Kinase Regulation

Author

Coyle, Scott M, Flores, Jonathan, and Lim, Wendell A

Subjects
Biochemistry and Cell Biology, Biological Sciences, 1.1 Normal biological development and functioning, Adaptor Proteins, Signal Transducing, Allosteric Regulation, Ascomycota, Enzyme Activation, Evolution, Molecular, Mitogen-Activated Protein Kinases, Models, Molecular, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Allosteric interactions provide precise spatiotemporal control over signaling proteins, but how allosteric activators and their targets coevolve is poorly understood. Here, we trace the evolution of two allosteric activator motifs within the yeast scaffold protein Ste5 that specifically target the mating MAP kinase Fus3. One activator (Ste5-VWA) provides pathway insulation and dates to the divergence of Fus3 from its paralog, Kss1; a second activator (Ste5-FBD) that tunes mating behavior is, in contrast, not conserved in most lineages. Surprisingly, both Ste5 activator motifs could regulate MAP kinases that diverged from Fus3 prior to the emergence of Ste5, suggesting that Ste5 activators arose by exploiting latent regulatory features already present in the MAPK ancestor. The magnitude of this latent allosteric potential drifts widely among pre-Ste5 MAP kinases, providing a pool of hidden phenotypic diversity that, when revealed by new activators, could lead to functional divergence and to the evolution of distinct signaling behaviors.

Published
2013

7. Conformational Control of the Ste5 Scaffold Protein Insulates Against MAP Kinase Misactivation

Author

Zalatan, Jesse G, Coyle, Scott M, Rajan, Saravanan, Sidhu, Sachdev S, and Lim, Wendell A

Subjects
Biochemistry and Cell Biology, Biological Sciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Adaptor Proteins, Signal Transducing, Enzyme Activation, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Models, Biological, Phosphorylation, Protein Conformation, Protein Interaction Domains and Motifs, Protein Kinases, Protein Precursors, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, General Science & Technology
Abstract

Cells reuse signaling proteins in multiple pathways, raising the potential for improper cross talk. Scaffold proteins are thought to insulate against such miscommunication by sequestering proteins into distinct physical complexes. We show that the scaffold protein Ste5, which organizes the yeast mating mitogen-activated protein kinase (MAPK) pathway, does not use sequestration to prevent misactivation of the mating response. Instead, Ste5 appears to use a conformation mechanism: Under basal conditions, an intramolecular interaction of the pleckstrin homology (PH) domain with the von Willebrand type A (VWA) domain blocks the ability to coactivate the mating-specific MAPK Fus3. Pheromone-induced membrane binding of Ste5 triggers release of this autoinhibition. Thus, in addition to serving as a conduit guiding kinase communication, Ste5 directly receives input information to decide if and when signal can be transmitted to mating output.

Published
2012

8. Coupled 5′ Nucleotide Recognition and Processivity in Xrn1-Mediated mRNA Decay

Author

Jinek, Martin, Coyle, Scott M, and Doudna, Jennifer A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Animals, Catalysis, Drosophila Proteins, Drosophila melanogaster, Exoribonucleases, Hydrolysis, Magnesium, Mutation, Nucleic Acid Conformation, Nucleotides, Phosphates, Phosphorylation, Protein Conformation, Protein Structure, Tertiary, RNA, Messenger, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Messenger RNA decay plays a central role in the regulation and surveillance of eukaryotic gene expression. The conserved multidomain exoribonuclease Xrn1 targets cytoplasmic RNA substrates marked by a 5' monophosphate for processive 5'-to-3' degradation by an unknown mechanism. Here, we report the crystal structure of an Xrn1-substrate complex. The single-stranded substrate is held in place by stacking of the 5'-terminal trinucleotide between aromatic side chains while a highly basic pocket specifically recognizes the 5' phosphate. Mutations of residues involved in binding the 5'-terminal nucleotide impair Xrn1 processivity. The substrate recognition mechanism allows Xrn1 to couple processive hydrolysis to duplex melting in RNA substrates with sufficiently long single-stranded 5' overhangs. The Xrn1-substrate complex structure thus rationalizes the exclusive specificity of Xrn1 for 5'-monophosphorylated substrates, ensuring fidelity of mRNA turnover, and posits a model for translocation-coupled unwinding of structured RNA substrates.

Published
2011

9. Structural and Biochemical Studies of a Fluoroacetyl-CoA-Specific Thioesterase Reveal a Molecular Basis for Fluorine Selectivity

Author

Weeks, Amy M, Coyle, Scott M, Jinek, Martin, Doudna, Jennifer A, and Chang, Michelle CY

Subjects
Biochemistry and Cell Biology, Biological Sciences, Generic health relevance, Acetyl Coenzyme A, Catalytic Domain, Crystallography, X-Ray, Escherichia coli, Fluorine, Kinetics, Protein Binding, Protein Conformation, Streptomyces, Substrate Specificity, Thermodynamics, Thiolester Hydrolases, Water, Medicinal and Biomolecular Chemistry, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

We have initiated a broad-based program aimed at understanding the molecular basis of fluorine specificity in enzymatic systems, and in this context, we report crystallographic and biochemical studies on a fluoroacetyl-coenzyme A (CoA) specific thioesterase (FlK) from Streptomyces cattleya. Our data establish that FlK is competent to protect its host from fluoroacetate toxicity in vivo and demonstrate a 10(6)-fold discrimination between fluoroacetyl-CoA (k(cat)/K(M) = 5 × 10⁷ M⁻¹ s⁻¹) and acetyl-CoA (k(cat)/K(M) = 30 M⁻¹ s⁻¹) based on a single fluorine substitution that originates from differences in both substrate reactivity and binding. We show that Thr 42, Glu 50, and His 76 are key catalytic residues and identify several factors that influence substrate selectivity. We propose that FlK minimizes interaction with the thioester carbonyl, leading to selection against acetyl-CoA binding that can be recovered in part by new C═O interactions in the T42S and T42C mutants. We hypothesize that the loss of these interactions is compensated by the entropic driving force for fluorinated substrate binding in a hydrophobic binding pocket created by a lid structure, containing Val 23, Leu 26, Phe 33, and Phe 36, that is not found in other structurally characterized members of this superfamily. We further suggest that water plays a critical role in fluorine specificity based on biochemical and structural studies focused on the unique Phe 36 "gate" residue, which functions to exclude water from the active site. Taken together, the findings from these studies offer molecular insights into organofluorine recognition and design of fluorine-specific enzymes.

Published
2010

10. Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation

Author

Jinek, Martin, Fabian, Marc R, Coyle, Scott M, Sonenberg, Nahum, and Doudna, Jennifer A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Amino Acid Substitution, Crystallography, X-Ray, Humans, MicroRNAs, Models, Molecular, Mutagenesis, Site-Directed, Poly(A)-Binding Protein I, Protein Binding, Protein Interaction Mapping, Protein Structure, Quaternary, RNA, Messenger, RNA-Binding Proteins, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

GW182-family proteins are essential for microRNA-mediated translational repression and deadenylation in animal cells. Here we show that a conserved motif in the human GW182 paralog TNRC6C interacts with the C-terminal domain of polyadenylate binding protein 1 (PABC) and present the crystal structure of the complex. Mutations at the complex interface impair mRNA deadenylation in mammalian cell extracts, suggesting that the GW182-PABC interaction contributes to microRNA-mediated gene silencing.

Published
2010

11. Direct Link between RACK1 Function and Localization at the Ribosome In Vivo

Author

Coyle, Scott M, Gilbert, Wendy V, and Doudna, Jennifer A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Adaptor Proteins, Signal Transducing, Crystallography, X-Ray, GTP-Binding Proteins, Membrane Proteins, Models, Molecular, Mutation, Nuclear Proteins, RNA-Binding Proteins, Ribosome Subunits, Small, Eukaryotic, Ribosomes, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Signal Transduction, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The receptor for activated C-kinase (RACK1), a conserved protein implicated in numerous signaling pathways, is a stoichiometric component of eukaryotic ribosomes located on the head of the 40S ribosomal subunit. To test the hypothesis that ribosome association is central to the function of RACK1 in vivo, we determined the 2.1-A crystal structure of RACK1 from Saccharomyces cerevisiae (Asc1p) and used it to design eight mutant versions of RACK1 to assess roles in ribosome binding and in vivo function. Conserved charged amino acids on one side of the beta-propeller structure were found to confer most of the 40S subunit binding affinity, whereas an adjacent conserved and structured loop had little effect on RACK1-ribosome association. Yeast mutations that confer moderate to strong defects in ribosome binding mimic some phenotypes of a RACK1 deletion strain, including increased sensitivity to drugs affecting cell wall biosynthesis and translation elongation. Furthermore, disruption of RACK1's position at the 40S ribosomal subunit results in the failure of the mRNA binding protein Scp160 to associate with actively translating ribosomes. These results provide the first direct evidence that RACK1 functions from the ribosome, implying a physical link between the eukaryotic ribosome and cell signaling pathways in vivo.

Published
2009

21. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): late breaking abstracts

Author

Althammer, Sonja, primary, Steele, Keith, additional, Rebelatto, Marlon, additional, Tan, Tze Heng, additional, Wiestler, Tobias, additional, Schmidt, Guenter, additional, Higgs, Brandon, additional, Li, Xia, additional, Shi, Li, additional, Jin, Xiaoping, additional, Antal, Joyce, additional, Gupta, Ashok, additional, Ranade, Koustubh, additional, Binning, Gerd, additional, Bellmunt, Joaquim, additional, de Wit, Ronald, additional, Vaughn, David J., additional, Fradet, Yves, additional, Lee, Jae Lyun, additional, Fong, Lawrence, additional, Vogelzang, Nicholas J., additional, Climent, Miguel A., additional, Petrylak, Daniel P., additional, Choueiri, Toni K., additional, Necchi, Andrea, additional, Gerritsen, Winald, additional, Gurney, Howard, additional, Quinn, David I., additional, Culine, Stéphane, additional, Sternberg, Cora N., additional, Mai, Yabing, additional, Puhlmann, Markus, additional, Perini, Rodolfo F., additional, Bajorin, Dean F., additional, Sharma, Padmanee, additional, Callahan, Margaret K., additional, Calvo, Emiliano, additional, Kim, Joseph W., additional, de Braud, Filipo, additional, Ott, Patrick A., additional, Bono, Petri, additional, Pillai, Rathi N., additional, Morse, Michael, additional, Le, Dung T., additional, Taylor, Matthew, additional, Spilliopoulou, Pavlina, additional, Bendell, Johanna, additional, Jaeger, Dirk, additional, Chan, Emily, additional, Antonia, Scott J., additional, Ascierto, Paolo A., additional, Hennicken, Delphine, additional, Tschaika, Marina, additional, Azrilevich, Alex, additional, Rosenberg, Jonathan, additional, Levy, Ofer, additional, Chan, Christopher, additional, Cojocaru, Gady, additional, Liang, Spencer, additional, Ophir, Eran, additional, Ganguly, Sudipto, additional, Toporik, Amir, additional, Kotturi, Maya, additional, Kfir, Tal Fridman, additional, Murter, Benjamin M., additional, Logronio, Kathryn, additional, Dassa, Liat, additional, Leung, Ling, additional, Greenwald, Shirley, additional, Azulay, Meir, additional, Kumar, Sandeep, additional, Alteber, Zoya, additional, Pan, Xiaoyu, additional, Machlenkin, Arthur, additional, Benita, Yair, additional, Drake, Andrew W., additional, Chajut, Ayelet, additional, Salomon, Ran, additional, Vankin, Ilan, additional, Safyon, Einav, additional, Hunter, John, additional, Levine, Zurit, additional, White, Mark, additional, Leidner, Rom, additional, Kang, Hyunseok, additional, Haddad, Robert, additional, Segal, Neil H., additional, Wirth, Lori J., additional, Ferris, Robert L., additional, Hodi, F. Stephen, additional, Sanborn, Rachel E., additional, Gajewski, Thomas F., additional, Sharfman, William, additional, McDonald, Dan, additional, Srivastava, Shivani, additional, Gu, Xuemin, additional, Phillips, Penny, additional, Passey, Chaitali, additional, Seiwert, Tanguy, additional, Habtetsion, Tsadik, additional, Zhou, Gang, additional, Sakellariou-Thompson, Donastas, additional, Haymaker, Cara, additional, Creasy, Caitlin, additional, Hurd, Mark, additional, Uraoka, Naohiro, additional, Canales, Jaime Rodriguez, additional, Koptez, Scott, additional, Hwu, Patrick, additional, Maitra, Anirban, additional, Bernatchez, Chantale, additional, Coyle, Scott M., additional, Roybel, Kole T., additional, Rupp, Levi J., additional, Santoro, Stephen P., additional, Secrest, Stephanie, additional, Spelman, Michael, additional, Ho, Hanson, additional, Gomes, Tina, additional, Tse, Tiffany, additional, Yung-Wu, Chia, additional, Taunton, Jack, additional, Lim, Wendell, additional, Emtage, Peter, additional, Moudgil, Tarsem, additional, Ballesteros-Merino, Carmen, additional, Hilton, Traci, additional, Paustian, Christopher, additional, Page, David, additional, Urba, Walter, additional, Fox, Bernard, additional, Bell, Bryan, additional, Patel, Ashish, additional, Olafsen, Tove, additional, Satpayev, Daulet, additional, Torgov, Michael, additional, Marchioni, Filippo, additional, Romero, Jason, additional, Jiang, Ziyue Karen, additional, Zamilpa, Charles, additional, Keppler, Jennifer S., additional, Mascioni, Alessandro, additional, Jia, Fang, additional, Lee, Chen-Yu, additional, Gudas, Jean, additional, Sullivan, Ryan J., additional, Hoshida, Yujin, additional, Logan, Theodore, additional, Khushalani, Nikhil, additional, Giobbie-Hurder, Anita, additional, Margolin, Kim, additional, Roder, Joanna, additional, Bhatt, Rupal, additional, Koon, Henry, additional, Olencki, Thomas, additional, Hutson, Thomas, additional, Curti, Brendan, additional, Blackmon, Shauna, additional, Mier, James W., additional, Puzanov, Igor, additional, Roder, Heinrich, additional, Stewart, John, additional, Amin, Asim, additional, Ernstoff, Marc S., additional, Clark, Joseph I., additional, Atkins, Michael B., additional, Kaufman, Howard L., additional, Sosman, Jeffrey, additional, Signoretti, Sabina, additional, McDermott, David F., additional, Anderson, Abraham A., additional, Milhem, Mohammed M., additional, Andtbacka, Robert H. I., additional, Minor, David, additional, Gorski, Kevin S., additional, Baker, Daniel M., additional, Hamid, Omid, additional, Akporiaye, Emmanuel, additional, Koguchi, Yoshinobu, additional, Sutcliffe, Kim, additional, Conder, Kristie, additional, Marron, Thomas, additional, Bhardwaj, Nina, additional, Hammerich, Linda, additional, George, Fiby, additional, Kim-Schulze, Seunghee, additional, Keler, Tibor, additional, Davis, Tom, additional, Crowley, Elizabeth, additional, Salazar, Andres, additional, Brody, Joshua, additional, Monjazeb, Arta, additional, Daly, Megan E., additional, Riess, Jonathan, additional, Li, Tianhong, additional, Murphy, William J., additional, Kelly, Karen, additional, Hu, Zhiwei, additional, Shen, Rulong, additional, Campbell, Amanda, additional, McMichael, Elizabeth, additional, Yu, Lianbo, additional, Ramaswam, Bhuvaneswari, additional, London, Cheryl A., additional, Xu, Tian, additional, Carson, William, additional, Kokolus, Kathleen M., additional, Repasky, Elizabeth A., additional, Schell, Todd D., additional, Drabick, Joseph D., additional, Messenheimer, David J., additional, Jensen, Shawn, additional, Rubinstein, Mark, additional, Andrijauskaite, Kristina, additional, Swiderska-syn, Marzena, additional, Lind, Kristin, additional, Choppin, Agnes, additional, Roell, Marina K., additional, Wrangle, John, additional, Rhode, Peter, additional, Wong, Hing, additional, Ahmad, Shamim, additional, Webb, Mason, additional, Abu-Eid, Rasha, additional, Shrimali, Rajeev, additional, Verma, Vivek, additional, Doroodchi, Atbin, additional, Berrong, Zuzana, additional, Yashar, David, additional, Samara, Raed, additional, Mkrtichyan, Mikayel, additional, Khleif, Samir, additional, Powell, Steven, additional, Gitau, Mark, additional, Sumey, Christopher, additional, Terrell, Andrew, additional, Lohr, Michele, additional, Nowak, Ryan K., additional, McGraw, Steven, additional, Jensen, Ash, additional, Blanchard, Miran, additional, Gold, Kathryn A., additional, Cohen, Ezra E. W., additional, Ellison, Christie, additional, Black, Lora, additional, Lee, John, additional, Spanos, William Chad, additional, Wennerberg, Erik, additional, Schwitzer, Emily, additional, Lhuillier, Claire, additional, Koelwyn, Graeme, additional, Hiner, Rebecca, additional, Jones, Lee, additional, Demaria, Sandra, additional, Amanda, Vandeveer, additional, Greiner, John W., additional, Schlom, Jeffrey, additional, Bookstaver, Michelle, additional, Jewell, Christopher M., additional, Gunderson, Andrew, additional, Boulmay, Brian, additional, Li, Rui, additional, Spieler, Bradley, additional, Happel, Kyle, additional, Feng, Zipei, additional, Dubay, Christopher, additional, Fisher, Brenda, additional, Aung, Sandra, additional, Mederos, Eileen, additional, Bifulco, Carlo B., additional, McNamara, Michael, additional, Bahjat, Keith, additional, Redmond, William, additional, Ochoa, Augusto, additional, Hu, Hong-Ming, additional, Mehta, Adi, additional, Lund-Johansen, Fridtjof, additional, Bedu-Addo, Frank, additional, Conn, Greg, additional, King, Michael, additional, Dutta, Panna, additional, Shepard, Robert, additional, Einstein, Mark, additional, Adams, Sylvia, additional, Wang, Ena, additional, Jin, Ping, additional, Novik, Yelena, additional, Morrison, Debra, additional, Oratz, Ruth, additional, Marincola, Franco M., additional, Stroncek, David, additional, Goldberg, Judith, additional, Formenti, Silvia C., additional, Galon, Jérôme, additional, Mlecnik, Bernhard, additional, Marliot, Florence, additional, Ou, Fang-Shu, additional, Lugli, Alessandro, additional, Zlobec, Inti, additional, Rau, Tilman T., additional, Nagtegaal, Iris D., additional, Vink-Borger, Elisa, additional, Hartmann, Arndt, additional, Geppert, Carol, additional, Roehrl, Michael H., additional, Bavi, Prashant, additional, Ohashi, Pamela S., additional, Wang, Julia Y., additional, Nguyen, Linh T., additional, Han, SeongJun, additional, MacGregor, Heather L., additional, Hafezi-Bakhtiari, Sara, additional, Wouters, Bradley G., additional, Kawakami, Yutaka, additional, Papivanova, Boryana, additional, Xu, Mingli, additional, Fujita, Tomonobu, additional, Hazama, Shoichi, additional, Suzuki, Nobuaki, additional, Nagano, Hiroaki, additional, Okuno, Kiyotaka, additional, Itoh, Kyogo, additional, Zavadova, Eva, additional, Vocka, Michal, additional, Spacek, Jan, additional, Petruzelka, Lubos, additional, Konopasek, Bohuslav, additional, Dundr, Pavel, additional, Skalova, Helena, additional, Torigoe, Toshihiko, additional, Sato, Noriyuki, additional, Furuhata, Tomohisa, additional, Takemasa, Ichiro, additional, Van den Eynde, Marc, additional, Jouret-Mourin, Anne, additional, Machiels, Jean-Pascal, additional, Fredriksen, Tessa, additional, Lafontaine, Lucie, additional, Buttard, Bénédicte, additional, Church, Sarah, additional, Maby, Pauline, additional, Angell, Helen, additional, Angelova, Mihaela, additional, Vasaturo, Angela, additional, Bindea, Gabriela, additional, Berger, Anne, additional, Lagorce, Christine, additional, Patel, Prabhu S., additional, Vora, Hemangini H., additional, Shah, Birva, additional, Patel, Jayendrakumar B., additional, Rajvik, Kruti N., additional, Pandya, Shashank J., additional, Shukla, Shilin N., additional, Wang, Yili, additional, Zhang, Guanjun, additional, Masucci, Giuseppe V., additional, Andersson, Emilia K., additional, Grizzi, Fabio, additional, Laghi, Luigi, additional, Botti, Gerardo, additional, Tatangelo, Fabiana, additional, Delrio, Paolo, additional, Cilberto, Gennaro, additional, Marincola, Franco, additional, Sargent, Daniel J., additional, Fox, Bernard A., additional, Algazi, Alain, additional, Tsai, Katy, additional, Rosenblum, Michael, additional, Nandoskar, Prachi, additional, Li, Amy, additional, Nonomura, John, additional, Takamura, Kathryn, additional, Dwyer, Mary, additional, Browning, Erica, additional, Talia, Reneta, additional, Twitty, Chris, additional, Gargosky, Sharron, additional, Campbell, Jean, additional, Le, Mai, additional, Pierce, Robert H., additional, Daud, Adil, additional, Gartrell, Robyn, additional, Marks, Douglas, additional, Stack, Edward, additional, Lu, Yan, additional, Izaki, Daisuke, additional, Beck, Kristen, additional, Jia, Dan Tong, additional, Armenta, Paul, additional, White-Stern, Ashley, additional, Fu, Yichun, additional, Blake, Zoe, additional, Taback, Bret, additional, Horst, Basil, additional, Saenger, Yvonne M., additional, Leonardo, Steven, additional, Gorden, Keith, additional, Fulton, Ross B., additional, Fraser, Kathryn, additional, Kangas, Takashi O., additional, Walsh, Richard, additional, Ertelt, Kathleen, additional, Graff, Jeremy, additional, Uhlik, Mark, additional, Sims, Jennifer S., additional, Lei, Liang, additional, Tsujiuchi, Takashi, additional, Bruce, Jeffrey N., additional, Canoll, Peter, additional, Tolcher, Anthony W, additional, Alley, Evan W, additional, Chichili, Gurunadh, additional, Canoll, Jan E, additional, Moore, Paul, additional, Bonvini, Ezio, additional, Johnson, Syd, additional, Shankar, Sadhna, additional, Vasselli, James, additional, Wigginton, Jon, additional, and Powderly, John, additional

Published
2016
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25. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): late breaking abstracts

Author

Althammer, Sonja, Steele, Keith, Rebelatto, Marlon, Tan, Tze Heng, Wiestler, Tobias, Schmidt, Guenter, Higgs, Brandon, Li, Xia, Shi, Li, Jin, Xiaoping, Antal, Joyce, Gupta, Ashok, Ranade, Koustubh, Binning, Gerd, Bellmunt, Joaquim, de Wit, Ronald, Vaughn, David J., Fradet, Yves, Lee, Jae Lyun, Fong, Lawrence, Vogelzang, Nicholas J., Climent, Miguel A., Petrylak, Daniel P., Choueiri, Toni K., Necchi, Andrea, Gerritsen, Winald, Gurney, Howard, Quinn, David I., Culine, Stéphane, Sternberg, Cora N., Mai, Yabing, Puhlmann, Markus, Perini, Rodolfo F., Bajorin, Dean F., Sharma, Padmanee, Callahan, Margaret K., Calvo, Emiliano, Kim, Joseph W., de Braud, Filipo, Ott, Patrick A., Bono, Petri, Pillai, Rathi N., Morse, Michael, Le, Dung T., Taylor, Matthew, Spilliopoulou, Pavlina, Bendell, Johanna, Jaeger, Dirk, Chan, Emily, Antonia, Scott J., Ascierto, Paolo A., Hennicken, Delphine, Tschaika, Marina, Azrilevich, Alex, Rosenberg, Jonathan, Levy, Ofer, Chan, Christopher, Cojocaru, Gady, Liang, Spencer, Ophir, Eran, Ganguly, Sudipto, Toporik, Amir, Kotturi, Maya, Kfir, Tal Fridman, Murter, Benjamin M., Logronio, Kathryn, Dassa, Liat, Leung, Ling, Greenwald, Shirley, Azulay, Meir, Kumar, Sandeep, Alteber, Zoya, Pan, Xiaoyu, Machlenkin, Arthur, Benita, Yair, Drake, Andrew W., Chajut, Ayelet, Salomon, Ran, Vankin, Ilan, Safyon, Einav, Hunter, John, Levine, Zurit, White, Mark, Leidner, Rom, Kang, Hyunseok, Haddad, Robert, Segal, Neil H., Wirth, Lori J., Ferris, Robert L., Hodi, F. Stephen, Sanborn, Rachel E., Gajewski, Thomas F., Sharfman, William, McDonald, Dan, Srivastava, Shivani, Gu, Xuemin, Phillips, Penny, Passey, Chaitali, Seiwert, Tanguy, Habtetsion, Tsadik, Zhou, Gang, Sakellariou-Thompson, Donastas, Haymaker, Cara, Creasy, Caitlin, Hurd, Mark, Uraoka, Naohiro, Canales, Jaime Rodriguez, Koptez, Scott, Hwu, Patrick, Maitra, Anirban, Bernatchez, Chantale, Coyle, Scott M., Roybel, Kole T., Rupp, Levi J., Santoro, Stephen P., Secrest, Stephanie, Spelman, Michael, Ho, Hanson, Gomes, Tina, Tse, Tiffany, Yung-Wu, Chia, Taunton, Jack, Lim, Wendell, Emtage, Peter, Moudgil, Tarsem, Ballesteros-Merino, Carmen, Hilton, Traci, Paustian, Christopher, Page, David, Urba, Walter, Fox, Bernard, Bell, Bryan, Patel, Ashish, Olafsen, Tove, Satpayev, Daulet, Torgov, Michael, Marchioni, Filippo, Romero, Jason, Jiang, Ziyue Karen, Zamilpa, Charles, Keppler, Jennifer S., Mascioni, Alessandro, Jia, Fang, Lee, Chen-Yu, Gudas, Jean, Sullivan, Ryan J., Hoshida, Yujin, Logan, Theodore, Khushalani, Nikhil, Giobbie-Hurder, Anita, Margolin, Kim, Roder, Joanna, Bhatt, Rupal, Koon, Henry, Olencki, Thomas, Hutson, Thomas, Curti, Brendan, Blackmon, Shauna, Mier, James W., Puzanov, Igor, Roder, Heinrich, Stewart, John, Amin, Asim, Ernstoff, Marc S., Clark, Joseph I., Atkins, Michael B., Kaufman, Howard L., Sosman, Jeffrey, Signoretti, Sabina, McDermott, David F., Anderson, Abraham A., Milhem, Mohammed M., Andtbacka, Robert H. 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26. Regulatable assembly of synthetic microtubule architectures using engineered MAP-IDR condensates.

Author

Chang CC and Coyle SM

Abstract

Microtubules filaments are assembled into higher-order structures and machines critical for cellular processes using microtubule-associated proteins (MAPs). However, the design of synthetic MAPs that direct the formation of new structures in cells is challenging, as nanoscale biochemical activities must be organized across micron length-scales. Here we develop synthetic MAP-IDR condensates (synMAPs) that provide tunable and regulatable assembly of higher-order microtubule structures in vitro and in mammalian cells. synMAPs harness a small microtubule-binding domain from oligodendrocytes (TPPP) whose activity can be synthetically rewired by interaction with condensate-forming IDR sequences. This combination allows synMAPs to self-organize multivalent structures that bind and bridge microtubules into synthetic architectures. Regulating the connection between the microtubule-binding and condensate-forming components allows synMAPs to act as nodes in more complex cytoskeletal circuits in which the formation and dynamics of the microtubule structure can be controlled by small molecules or cell-signaling inputs. By systematically testing a panel of synMAP circuit designs, we define a two-level control scheme for dynamic assembly of microtubule architectures at the nanoscale (via microtubule-binding) and microscale (via condensate formation). synMAPs provide a compact and rationally engineerable starting point for the design of more complex microtubule architectures and cellular machines.

Published
2023
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27. Comparative profiling of cellular gait on adhesive micropatterns defines statistical patterns of activity that underlie native and cancerous cell dynamics.

Author

Ahn JC and Coyle SM

Abstract

Cell dynamics are powered by patterns of activity, but it is not straightforward to quantify these patterns or compare them across different environmental conditions or cell-types. Here we digitize the long-term shape fluctuations of metazoan cells grown on micropatterned fibronectin islands to define and extract statistical features of cell dynamics without the need for genetic modification or fluorescence imaging. These shape fluctuations generate single-cell morphological signals that can be decomposed into two major components: a continuous, slow-timescale meandering of morphology about an average steady-state shape; and short-lived "events" of rapid morphology change that sporadically occur throughout the timecourse. By developing statistical metrics for each of these components, we used thousands of hours of single-cell data to quantitatively define how each axis of cell dynamics was impacted by environmental conditions or cell-type. We found the size and spatial complexity of the micropattern island modulated the statistics of morphological events-lifetime, frequency, and orientation-but not its baseline shape fluctuations. Extending this approach to profile a panel of triple negative breast cancer cell-lines, we found that different cell-types could be distinguished from one another along specific and unique statistical axes of their behavior. Our results suggest that micropatterned substrates provide a generalizable method to build statistical profiles of cell dynamics to classify and compare emergent cell behaviors., Competing Interests: Competing interests: None.

Published
2023
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