Identification of a peptide antagonist of the <scp>FGF</scp>1–<scp>FGFR</scp>1 signaling axis by phage display selection

Lipok, Magdalena; Szlachcic, Anna; Kindela, Kinga; Czyrek, Aleksandra; Otlewski, Jacek

doi:10.1002/2211-5463.12618

Cited by 18 publications

(12 citation statements)

References 37 publications

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“…The blockage of the FGF-1 signaling pathway causes a cell cycle arrest in phase G0/G1, thus decreased cancer cell proliferation. It also reduces tumor growth and occurring metastasis [167,168]. Another metabolite described before as a tumor promotor 3-HAA also seems to be a double-edged compound.…”

Section: Other Carcinogenesis Modulating Effects Of Trp Metabolitesmentioning

confidence: 82%

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

Kwiatkowska

Hermanowicz

Przybyszewska-Podstawka

et al. 2021

Cancers

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Background: The recently discovered phenomenon that cancer cells can avoid immune response has gained scientists' interest. One of the pathways involved in this process is tryptophan (TRP) metabolism through the kynurenine pathway (KP). Individual components involved in TRP conversion seem to contribute to cancerogenesis both through a direct impact on cancer cells and the modulation of immune cell functionality. Due to this fact, this pathway may serve as a target for immunotherapy and attempts are being made to create novel compounds effective in cancer treatment. However, the results obtained from clinical trials are not satisfactory, which raises questions about the exact role of KP elements in tumorigenesis. An increasing number of experiments reveal that TRP metabolites may either be tumor promoters and suppressors and this is why further research in this field is highly needed. The aim of this study is to present KP as a modulator of cancer development through multiple mechanisms and to point to its ambiguity, which may be a reason for failures in treatment based on the inhibition of tryptophan metabolism

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Section: Other Carcinogenesis Modulating Effects Of Trp Metabolitesmentioning

confidence: 82%

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

Kwiatkowska

Hermanowicz

Przybyszewska-Podstawka

et al. 2021

Cancers

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“…Fibroblast growth factor receptor 1 (FGFR1) is overexpressed in lung and breast cancers and therefore drugs targeting FGF1/FGFR1 PPI could be an alternative to small-molecule tyrosine kinase inhibitors for handling FGFR1-dependent cancers. In this respect, the group of Jacek Otlewski described the selection of cyclic peptides able to disrupt the FGF1/FGFR1 interaction prepared by phage display [ 52 ]. The most potent cyclic peptide 10 , but not its linear peptide equivalent, is able to inhibit the FGFR1 downstream signaling and the FGF1-induced cell proliferation in cell expressing FGFR1.…”

Section: Main Methodologies To Cyclic and Macrocyclic Peptidesmentioning

confidence: 99%

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

2021

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Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes.

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“…Activity of RTKs can be downregulated also through the action of antagonist ligands or molecules able to bind to the extracellular site of the receptor where the ligands normally bind, at the ligand-RTK interface or at the intracellular domain, usually at the KD [85]. An antagonist counteracts the action of a natural ligand, an agonist, partial agonist, or an inverse agonist.…”

Section: Clinical Aspects Of Rtk Downregulationmentioning

confidence: 99%

“…In fact, it interacts at the FGF1-FGFR1 interface. Noteworthy, F8 affects FGF1-FGFR1 interaction, inhibits FGFR1 downstream signaling, and FGF1-induced cell proliferation [85].…”

Section: Clinical Aspects Of Rtk Downregulationmentioning

confidence: 99%

All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal

Margiotta

2021

IJMS

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Receptor tyrosine kinases (RTKs) are membrane receptors that regulate many fundamental cellular processes. A tight regulation of RTK signaling is fundamental for development and survival, and an altered signaling by RTKs can cause cancer. RTKs are localized at the plasma membrane (PM) and the major regulatory mechanism of signaling of RTKs is their endocytosis and degradation. In fact, RTKs at the cell surface bind ligands with their extracellular domain, become active, and are rapidly internalized where the temporal extent of signaling, attenuation, and downregulation are modulated. However, other mechanisms of signal attenuation and termination are known. Indeed, inhibition of RTKs’ activity may occur through the modulation of the phosphorylation state of RTKs and the interaction with specific proteins, whereas antagonist ligands can inhibit the biological responses mediated by the receptor. Another mechanism concerns the expression of endogenous inactive receptor variants that are deficient in RTK activity and take part to inactive heterodimers or hetero-oligomers. The downregulation of RTK signals is fundamental for several cellular functions and the homeostasis of the cell. Here, we will review the mechanisms of signal attenuation and termination of RTKs, focusing on FGFRs.

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Identification of a peptide antagonist of the FGF1–FGFR1 signaling axis by phage display selection

Cited by 18 publications

References 37 publications

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal

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