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Altering FAK-paxillin interactions reduces adhesion, migration and invasion processes
Thérèse B Deramaudt1, Denis Dujardin1, Fanny Noulet1
1CNRS, UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Illkirch, France; Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
Plos One
|March 20, 2014
Summary
Targeting focal adhesion kinase (FAK) interactions with paxillin disrupts FAK localization and downstream signaling, inhibiting cell migration and invasion. This approach offers a novel strategy for developing FAK inhibitors.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Focal adhesion kinase (FAK) is crucial for integrin-mediated cell adhesion and signaling.
- FAK plays a significant role in cancer metastasis, including cell adhesion, migration, and invasion.
- Existing small molecule inhibitors target FAK's catalytic activity.
Purpose of the Study:
- To investigate if inhibiting FAK's targeting to focal adhesions (FAs) is an effective strategy to block downstream pathways.
- To explore the impact of disrupting FAK-paxillin interactions on FAK signaling and cellular functions.
Main Methods:
- Constructed a FAK mutant unable to bind paxillin using mutagenesis.
- Analyzed FAK localization, phosphorylation, and downstream target phosphorylation.
- Assessed FA dynamics, cell adhesion, migration, and invasion capabilities.
Main Results:
- The FAK mutant failed to localize to FAs, reducing FAK and target phosphorylation (paxillin, p130Cas).
- FA dynamics were altered, leading to inhibited cell adhesion, migration, and invasion.
- Cells expressing the FAK mutant showed reduced migration compared to FAK-/- cells, with decreased phospho-Src and phospho-p130Cas at FAs.
Conclusions:
- Targeting FAK-paxillin interactions effectively reduces FAK signaling.
- Disrupting FAK localization to FAs is a viable strategy to inhibit FAK downstream pathways.
- This interaction represents a promising target for novel FAK inhibitor development.
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