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Current Signal Transduction Therapy

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ISSN (Print): 1574-3624
ISSN (Online): 2212-389X

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Research Article

Mutation S249C of FGFR3b Promotes Bladder Cancer through Downstream Signaling Proteins FRS2 and FRS3: A Computational Approach

Author(s): Aisha Ali, Alwisha Lateef, Zuha Waheed, Mishal Waseem, Tahreem Zaheer, Miriam K Gomez, Roman Blaheta and Saira Justin*

Volume 18, Issue 2, 2023

Published on: 29 August, 2023

Article ID: e100823219610 Pages: 11

DOI: 10.2174/1574362418666230810094626

Price: $65

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Abstract

Background: Bladder cancer is the 9th most prevalent malignancy worldwide. Fibroblast Growth Factor Receptor 3b (FGFR3b), involved in cell proliferation, differentiation, and migration, is a mutations hotspot for bladder cancer with the most prevalent aberration being S249C.

Objective: Impact of S249C of FGFR3b on bladder tumorigenesis via immediate downstream adapter proteins, Fibroblast Growth Factor Receptor Substrate (FRS2 and FRS3) is analyzed computationally.

Methods: Wildtype FGFR3b monomer was modeled using I-TASSER and Phyre2. Whereas, S249C mutation was introduced via DynaMut. Wildtype FGFR3b homodimer and mutant heterodimer were structured and docked with downstream proteins using HADDOCK. PDBSum was used to study the amino acid residues involved in intermolecular and intramolecular interactions.

Results: Parameters of molecular flexibility and interatomic interactions predicted S249C heterodimer mutation of FGFR3b to be stable. Furthermore, docking with FRS2 protein revealed greater stability and higher binding affinity for S249C heterodimer mutant compared to wildtype homodimer. However, FRS3 docking showed a negligible decline in binding affinity for the S249C mutation but based on Van der Waal’s energy and insights into the interacting residues, it was revealed that these interactions might be stronger and for longer duration in comparison to the wildtype homodimer.

Conclusion: S249C heterodimer mutation of FGFR3b is predicted to be stable with a tumorigenic potential where FRS2 and FRS3 might be among the key players of altered downstream signaling. Further investigations are required for a detailed picture.

Graphical Abstract

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