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785 results on '"Gertler, Frank"'

2. Cutting Edge: Loss of T Cell RIAM Precludes Conjugate Formation with APC and Prevents Immune-Mediated Diabetes.

Author

Lagarrigue, Frederic, Gertler, Frank B, Ginsberg, Mark H, and Cantor, Joseph M

Subjects
Diabetes, Prevention, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Adoptive Transfer, Animals, Antigen-Presenting Cells, Cell Proliferation, Cells, Cultured, Cytotoxicity, Immunologic, Diabetes Mellitus, Type 1, Humans, Immunological Synapses, Lymphocyte Function-Associated Antigen-1, Membrane Proteins, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Talin, Immunology
Abstract

Rap1-interacting adaptor molecule (RIAM) is a Rap1 effector that mediates the recruitment of talin to integrins, thereby supporting their activation. In this study, we investigated the role of RIAM in an adoptive transfer model for type I diabetes and report that RIAM expression in T cells is necessary for diabetes development. Loss of RIAM did not prevent lymphocyte recruitment to draining lymph nodes 24 h after transfer, but it was required for Ag-driven proliferation and cytotoxic killing. RIAM is recruited to immune synapses along with talin and LFA-1, and loss of RIAM profoundly suppresses Ag-dependent conjugate formation in primary naive and effector T cells. These data identify the requirement of RIAM for formation of immunological synapses and in resulting T cell functions in autoimmunity. Moreover, because RIAM-null mice are healthy, fertile, and display no bleeding abnormalities, our results identify RIAM and its regulators as potential targets for therapies of T cell-mediated autoimmunity.

Published
2017

3. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells.

Author

Meyer, Aaron S, Miller, Miles A, Gertler, Frank B, and Lauffenburger, Douglas A

Subjects
Cell Line, Tumor, Humans, Breast Neoplasms, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Receptor, IGF Type 1, Receptor, Insulin, Receptors, Platelet-Derived Growth Factor, Proto-Oncogene Proteins, Antigens, CD, Signal Transduction, Cell Movement, Gene Expression Regulation, Neoplastic, Female, Proto-Oncogene Proteins c-met, Transcriptional Activation, ErbB Receptors, Biochemistry and Cell Biology
Abstract

The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)-associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor-targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)-elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling.

Published
2013

4. 2D protrusion but not motility predicts growth factor–induced cancer cell migration in 3D collagen

Author

Meyer, Aaron S, Hughes-Alford, Shannon K, Kay, Jennifer E, Castillo, Amalchi, Wells, Alan, Gertler, Frank B, and Lauffenburger, Douglas A

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Collagen, Female, Humans, Intercellular Signaling Peptides and Proteins, Ligands, Neoplasms, Receptor Protein-Tyrosine Kinases, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Growth factor-induced migration is a critical step in the dissemination and metastasis of solid tumors. Although differences in properties characterizing cell migration on two-dimensional (2D) substrata versus within three-dimensional (3D) matrices have been noted for particular growth factor stimuli, the 2D approach remains in more common use as an efficient surrogate, especially for high-throughput experiments. We therefore were motivated to investigate which migration properties measured in various 2D assays might be reflective of 3D migratory behavioral responses. We used human triple-negative breast cancer lines stimulated by a panel of receptor tyrosine kinase ligands relevant to mammary carcinoma progression. Whereas 2D migration properties did not correlate well with 3D behavior across multiple growth factors, we found that increased membrane protrusion elicited by growth factor stimulation did relate robustly to enhanced 3D migration properties of the MDA-MB-231 and MDA-MB-157 lines. Interestingly, we observed this to be a more reliable relationship than cognate receptor expression or activation levels across these and two additional mammary tumor lines.

Published
2012

5. The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics.

Author

Nakatsu, Fubito, Perera, Rushika, Lucast, Louise, Zoncu, Roberto, Domin, Jan, Gertler, Frank, Toomre, Derek, and De Camilli, Pietro

Subjects
Animals, COS Cells, Chlorocebus aethiops, Clathrin, Coated Pits, Cell-Membrane, Endocytosis, Inositol Polyphosphate 5-Phosphatases, Mice, Phosphatidylinositol-3, 4, 5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases
Abstract

Phosphatidylinositol (PI) 4,5-bisphosphate (PI(4,5)P(2)) and its phosphorylated product PI 3,4,5-triphosphate (PI(3,4,5)P(3)) are two major phosphoinositides concentrated at the plasma membrane. Their levels, which are tightly controlled by kinases, phospholipases, and phosphatases, regulate a variety of cellular functions, including clathrin-mediated endocytosis and receptor signaling. In this study, we show that the inositol 5-phosphatase SHIP2, a negative regulator of PI(3,4,5)P(3)-dependent signaling, also negatively regulates PI(4,5)P(2) levels and is concentrated at endocytic clathrin-coated pits (CCPs) via interactions with the scaffold protein intersectin. SHIP2 is recruited early at the pits and dissociates before fission. Both knockdown of SHIP2 expression and acute production of PI(3,4,5)P(3) shorten CCP lifetime by enhancing the rate of pit maturation, which is consistent with a positive role of both SHIP2 substrates, PI(4,5)P(2) and PI(3,4,5)P(3), on coat assembly. Because SHIP2 is a negative regulator of insulin signaling, our findings suggest the importance of the phosphoinositide metabolism at CCPs in the regulation of insulin signal output.

Published
2010

13. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila.

Author

Kazantsev, Aleksey, Walker, Heli A, Slepko, Natalia, Bear, James E, Preisinger, Elizabeth, Steffan, Joan S, Zhu, Ya-Zhen, Gertler, Frank B, Housman, David E, Marsh, J Lawrence, and Thompson, Leslie M

Subjects
Neurons, Cells, Cultured, Cell Line, COS Cells, Animals, Drosophila, Glutathione Transferase, Peptides, Luminescent Proteins, Green Fluorescent Proteins, Nerve Tissue Proteins, Nuclear Proteins, Recombinant Fusion Proteins, DNA, Complementary, Epitopes, Microscopy, Fluorescence, Microscopy, Video, Blotting, Western, Transfection, Suppression, Genetic, Repetitive Sequences, Amino Acid, Protein Structure, Tertiary, Protein Binding, Kinetics, Mutation, Plasmids, Time Factors, Molecular Sequence Data, Photoreceptor Cells, Invertebrate, Cells, Cultured, DNA, Complementary, Microscopy, Fluorescence, Video, Blotting, Western, Suppression, Genetic, Repetitive Sequences, Amino Acid, Protein Structure, Tertiary, Photoreceptor Cells, Invertebrate, Neurodegenerative, Rare Diseases, Huntington's Disease, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Huntington disease is caused by the expansion of a polyglutamine repeat in the Huntingtin protein (Htt) that leads to degeneration of neurons in the central nervous system and the appearance of visible aggregates within neurons. We have developed and tested suppressor polypeptides that bind mutant Htt and interfere with the process of aggregation in cell culture. In a Drosophila model, the most potent suppressor inhibits both adult lethality and photoreceptor neuron degeneration. The appearance of aggregates in photoreceptor neurons correlates strongly with the occurrence of pathology, and expression of suppressor polypeptides delays and limits the appearance of aggregates and protects photoreceptor neurons. These results suggest that targeting the protein interactions leading to aggregate formation may be beneficial for the design and development of therapeutic agents for Huntington disease.

Published
2002

16. Supplementary Figure S2 from Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Author

Miller, Miles A., primary, Oudin, Madeleine J., primary, Sullivan, Ryan J., primary, Wang, Stephanie J., primary, Meyer, Aaron S., primary, Im, Hyungsoon, primary, Frederick, Dennie T., primary, Tadros, Jenny, primary, Griffith, Linda G., primary, Lee, Hakho, primary, Weissleder, Ralph, primary, Flaherty, Keith T., primary, Gertler, Frank B., primary, and Lauffenburger, Douglas A., primary

Published
2023
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17. Supplementary Methods, Figure Legends from Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Author

Miller, Miles A., primary, Oudin, Madeleine J., primary, Sullivan, Ryan J., primary, Wang, Stephanie J., primary, Meyer, Aaron S., primary, Im, Hyungsoon, primary, Frederick, Dennie T., primary, Tadros, Jenny, primary, Griffith, Linda G., primary, Lee, Hakho, primary, Weissleder, Ralph, primary, Flaherty, Keith T., primary, Gertler, Frank B., primary, and Lauffenburger, Douglas A., primary

Published
2023
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18. Data from Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance

Author

Miller, Miles A., primary, Oudin, Madeleine J., primary, Sullivan, Ryan J., primary, Wang, Stephanie J., primary, Meyer, Aaron S., primary, Im, Hyungsoon, primary, Frederick, Dennie T., primary, Tadros, Jenny, primary, Griffith, Linda G., primary, Lee, Hakho, primary, Weissleder, Ralph, primary, Flaherty, Keith T., primary, Gertler, Frank B., primary, and Lauffenburger, Douglas A., primary

Published
2023
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19. Supplementary Figure S1 from Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

Author

Oudin, Madeleine J., primary, Jonas, Oliver, primary, Kosciuk, Tatsiana, primary, Broye, Liliane C., primary, Guido, Bruna C., primary, Wyckoff, Jeff, primary, Riquelme, Daisy, primary, Lamar, John M., primary, Asokan, Sreeja B., primary, Whittaker, Charlie, primary, Ma, Duanduan, primary, Langer, Robert, primary, Cima, Michael J., primary, Wisinski, Kari B., primary, Hynes, Richard O., primary, Lauffenburger, Douglas A., primary, Keely, Patricia J., primary, Bear, James E., primary, and Gertler, Frank B., primary

Published
2023
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20. Supplementary Video S2 from Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

Author

Oudin, Madeleine J., primary, Jonas, Oliver, primary, Kosciuk, Tatsiana, primary, Broye, Liliane C., primary, Guido, Bruna C., primary, Wyckoff, Jeff, primary, Riquelme, Daisy, primary, Lamar, John M., primary, Asokan, Sreeja B., primary, Whittaker, Charlie, primary, Ma, Duanduan, primary, Langer, Robert, primary, Cima, Michael J., primary, Wisinski, Kari B., primary, Hynes, Richard O., primary, Lauffenburger, Douglas A., primary, Keely, Patricia J., primary, Bear, James E., primary, and Gertler, Frank B., primary

Published
2023
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22. Data from Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

Author

Oudin, Madeleine J., primary, Jonas, Oliver, primary, Kosciuk, Tatsiana, primary, Broye, Liliane C., primary, Guido, Bruna C., primary, Wyckoff, Jeff, primary, Riquelme, Daisy, primary, Lamar, John M., primary, Asokan, Sreeja B., primary, Whittaker, Charlie, primary, Ma, Duanduan, primary, Langer, Robert, primary, Cima, Michael J., primary, Wisinski, Kari B., primary, Hynes, Richard O., primary, Lauffenburger, Douglas A., primary, Keely, Patricia J., primary, Bear, James E., primary, and Gertler, Frank B., primary

Published
2023
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23. Supplementary Figure Legends from Tumor Cell–Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression

Author

Oudin, Madeleine J., primary, Jonas, Oliver, primary, Kosciuk, Tatsiana, primary, Broye, Liliane C., primary, Guido, Bruna C., primary, Wyckoff, Jeff, primary, Riquelme, Daisy, primary, Lamar, John M., primary, Asokan, Sreeja B., primary, Whittaker, Charlie, primary, Ma, Duanduan, primary, Langer, Robert, primary, Cima, Michael J., primary, Wisinski, Kari B., primary, Hynes, Richard O., primary, Lauffenburger, Douglas A., primary, Keely, Patricia J., primary, Bear, James E., primary, and Gertler, Frank B., primary

Published
2023
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25. Data from Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes

Author

Rohani, Nazanin, primary, Hao, Liangliang, primary, Alexis, Maria S., primary, Joughin, Brian A., primary, Krismer, Konstantin, primary, Moufarrej, Mira N., primary, Soltis, Anthony R., primary, Lauffenburger, Douglas A., primary, Yaffe, Michael B., primary, Burge, Christopher B., primary, Bhatia, Sangeeta N., primary, and Gertler, Frank B., primary

Published
2023
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26. Supplementary data and tables from Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes

Author

Rohani, Nazanin, primary, Hao, Liangliang, primary, Alexis, Maria S., primary, Joughin, Brian A., primary, Krismer, Konstantin, primary, Moufarrej, Mira N., primary, Soltis, Anthony R., primary, Lauffenburger, Douglas A., primary, Yaffe, Michael B., primary, Burge, Christopher B., primary, Bhatia, Sangeeta N., primary, and Gertler, Frank B., primary

Published
2023
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28. Figure S2 from Acidification of Tumor at Stromal Boundaries Drives Transcriptome Alterations Associated with Aggressive Phenotypes

Author

Rohani, Nazanin, primary, Hao, Liangliang, primary, Alexis, Maria S., primary, Joughin, Brian A., primary, Krismer, Konstantin, primary, Moufarrej, Mira N., primary, Soltis, Anthony R., primary, Lauffenburger, Douglas A., primary, Yaffe, Michael B., primary, Burge, Christopher B., primary, Bhatia, Sangeeta N., primary, and Gertler, Frank B., primary

Published
2023
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31. Supplementary Figures S1-S9 and List of Supplementary Tables from Adaptive and Reversible Resistance to Kras Inhibition in Pancreatic Cancer Cells

Author

Chen, Pan-Yu, primary, Muzumdar, Mandar Deepak, primary, Dorans, Kimberly Judith, primary, Robbins, Rebecca, primary, Bhutkar, Arjun, primary, del Rosario, Amanda, primary, Mertins, Philipp, primary, Qiao, Jana, primary, Schafer, Anette Claudia, primary, Gertler, Frank, primary, Carr, Steven, primary, and Jacks, Tyler, primary

Published
2023
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