Semirational design of a potent, artificial agonist of fibroblast growth factor receptors

Ballinger, Marcus; Shyamala, Venkatakrishna; Forrest, L D; Deuter-Reinhard, Maja; Doyle, Laura V.; Wang, J X; Panganiban-Lustan, L; Stratton, Jennifer; Apell, Gerald; Winter, J A; Doyle, Michael; Rosenberg, Steven; Kavanaugh, W M

doi:10.1038/70746

Cited by 61 publications

(35 citation statements)

References 36 publications

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“…In another case, a 19-residue peptide was selected for binding an FGFR. When the peptide was dimerized by fusion to the c-Jun leucine zipper, it activated the FGFR in presence of a synergistic binder, heparin, with a potency similar to that of FGF (64). Thus, small mimetics can be found for the cytokine receptors.…”

Section: Mechanisms Of Horizontal Signaling Complexesmentioning

confidence: 99%

Mechanistic Diversity of Cytokine Receptor Signaling Across Cell Membranes

Stroud

Wells

2004

Sci. STKE

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Circulating cytokines bind to specific receptors on the cell outer surface to evoke responses inside the cell. Binding of cytokines alters the association between receptor molecules that often cross the membrane only once in a single alpha-helical segment. As a consequence, association of protein domains on the inside of the membrane are also altered. Increasing evidence suggests that an initial "off-state" of associated receptors is perturbed, and brought to an activated state that leads to intracellular signaling and eventually effects a change in DNA transcription. The initial detection event that transduces the change in receptor association is sensitive to both proximity and orientation of the receptors, and probably also to the time that the activated state or receptor association is maintained. Ultimately, a cascade of phosphorylation events is triggered. The initial kinases are sometimes part of the intracellular domains of the receptors. The kinases can also be separate proteins that may be pre-associated with intracellular domains of the receptors, or can be recruited after the intracellular association of the activated receptors. We focus here on each of the cases for which structures of the activated cytokine-receptor complexes are known, in a search for underlying mechanisms. The variations in modes of association, stoichiometries of receptors and cytokines, and orientations before and after activation of these receptors are almost as great as the number of complexes themselves. The principles uncovered nevertheless illustrate the basis for high specificity and fidelity in cytokine-mediated signaling.

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Section: Mechanisms Of Horizontal Signaling Complexesmentioning

confidence: 99%

Mechanistic Diversity of Cytokine Receptor Signaling Across Cell Membranes

Stroud

Wells

2004

Sci. STKE

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“…A 26-residue peptide identified by phage display specifically bound FGF receptor (FGFR) 1c extracellular domain, but had no homology with FGFs. When fused with the c-jun leucine zipper domain, which binds heparin and forms homodimers, the polypeptide specifically reproduced the mitogenic and morphogenic activities of basic FGF with similar potency (EC50 = 240 pM) [38].…”

Section: Cytokine and Growth Factor Receptorsmentioning

confidence: 99%

Identification of Tumor Targeting Agents by Phage Display

Romanov¹

2005

MCRO

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Techniques of the phage display libraries construction have been dramatically improved. This allowed researchers to expand the application field to cancer biology. Tumor targeting -selective delivery of active compounds to the tumor sites for cancer imaging or treatment presents obvious advantages as compared to chemotherapeutic approachkilling rapidly proliferating cells. Tumor-avid peptides can be efficiently identified by means of phage display libraries.The most direct application of peptide-protein phage-displayed libraries is a selection of ligands for individual molecules important for cancer development. This includes identification of ligands for cell surface molecules, mapping proteinprotein interactions and delineation of signal transduction pathways. Enzymes substrates and modulators of their activity can also be identified via phage display-based selection. Recently, more complicated than individual molecules, biological systems started to be used as targets for biopanning. This includes combination of soluble proteins, cellular surfaces and even vasculature or surface of whole organs. In addition, construction and application of cDNA expression libraries in phage-based vectors recently received appreciation. The use of the phage as a vector for targeted gene therapy is also considered. In the current review, we will discuss the selection of tumor-targeting peptides and proteins identified by means of random peptide and cDNA phage-displayed libraries.

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“…In this study FGF2 was used as an example to help improve and characterise the coating platform but is unlikely to be effective for systemic applications in vivo as a whole growth factor molecule. To target these receptors more effectively, small fragments or peptides could be used [32]. Lower affinity peptides should have greater selectivity through the avidity effect of multiple peptides displayed on the surface of a vector.…”

Section: H Exposure To Cells With Transgene Expression Evaluated Aftementioning

confidence: 99%