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Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
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Spatial cycles mediated by UNC119 solubilisation maintain Src family kinases plasma membrane localisation
Antonios D Konitsiotis1, Lisaweta Roßmannek1, Angel Stanoev1
1Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.
Nature Communications
|July 26, 2017
Summary
Peripheral membrane protein tyrosine kinases, Src family kinases (SFKs), are maintained at the plasma membrane through spatial cycles of solubilization and transport. The protein UNC119 is crucial for sequestering SFKs, impacting their signaling activity.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Src family protein tyrosine kinases (SFKs) are crucial for relaying growth factor signals.
- Maintaining SFK enrichment and activity at the plasma membrane is essential for signal transduction.
- SFKs are peripheral membrane proteins requiring specific mechanisms for localization.
Purpose of the Study:
- To elucidate the spatial cycles of solubilization, membrane compartment trapping, and vesicular transport that maintain SFK enrichment at the plasma membrane.
- To identify the roles of UNC119, Arl2/3, and palmitoyl acyl-transferase in SFK localization and activity.
- To explore the therapeutic potential of targeting UNC119 for oncogenic SFK signaling.
Main Methods:
- Investigated spatial cycles of SFK solubilization, trapping, and transport.
- Utilized UNC119 knockdown to assess its impact on SFK localization and signaling.
- Examined the roles of Arl2/3 activity and palmitoyl acyl-transferase in SFK trafficking.
Main Results:
- UNC119 sequesters myristoylated SFKs, enhancing their diffusion and release on recycling endosomes via Arl2/3.
- Src is electrostatically trapped on recycling endosomes, while Fyn is kinetically trapped on the Golgi.
- Vesicular trafficking from endosomes and Golgi restores SFK enrichment at the plasma membrane.
- UNC119 knockdown disrupts SFK localization and signaling activity.
Conclusions:
- Spatial cycles involving UNC119, membrane compartments, and vesicular transport are critical for maintaining plasma membrane localization and activity of SFKs.
- UNC119 plays a key role in sequestering and trafficking SFKs, essential for signal transduction.
- UNC119 represents a potential drug target for modulating oncogenic SFK signaling.
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