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Published on: March 1, 2017
Cellular responses to FGF1 are modulated by palmitoylation of the docking protein FRS2α
Abstract:
An important mechanism by which receptor tyrosine kinases (RTKs) mediate cellular responses involves the formation of signaling complexes through direct interactions with membrane-associated docking proteins, followed by phosphorylation of multiple tyrosine residues. These docking proteins recruit and activate downstream signaling molecules and enzymes following ligand stimulation. The docking protein FRS2α has been established as a major signaling hub activated by fibroblast growth factors (FGFs), neurotrophic factors, and other extracellular cues. Here, we show that palmitoylation of FRS2α at two sites is essential for stabilizing its myristoylation-dependent association with the plasma membrane. FGF1-induced MAPK activation and other cellular responses are partially restored in cells expressing FRS2α mutants deficient in either one of the two palmitoylation sites. However full restoration of signal strength including MAPK response and other FGF1-induced cellular activities requires palmitoylation at both FRS2α sites. In addition to enhancing signaling robustness, anchoring of FRS2α to the plasma membrane creates a structural platform for assembling multi-protein complexes essential for cytoskeletal reorganization associated with membrane ruffling, macropinocytosis, and other FGF1-induced processes. Finally, we demonstrate that while PC12 cells lacking FRS2α or deficient in FRS2α palmitoylation can proliferate, FGF1-induced neuronal differentiation strictly depends on the palmitoylation of the docking protein.
Insights
Palmitoylation of the FRS2α docking protein stabilizes its membrane association, enhancing fibroblast growth factor (FGF) signaling. Full FGF1-induced cellular responses and neuronal differentiation require dual palmitoylation sites on FRS2α.
Area of Science:
- Cellular signaling
- Molecular biology
- Biochemistry
Background:
- Receptor tyrosine kinases (RTKs) mediate cellular responses via signaling complexes with docking proteins.
- FRS2α is a key signaling hub activated by fibroblast growth factors (FGFs) and other cues.
- Docking proteins recruit and activate downstream signaling molecules after ligand stimulation.
Purpose of the Study:
- To investigate the role of FRS2α palmitoylation in stabilizing its plasma membrane association.
- To determine the impact of FRS2α palmitoylation on FGF1-induced cellular responses, including MAPK activation and neuronal differentiation.
- To elucidate how FRS2α anchoring to the plasma membrane facilitates multi-protein complex assembly.
Main Methods:
- Site-directed mutagenesis to create FRS2α mutants deficient in palmitoylation.
- Cellular assays to assess MAPK activation and other FGF1-induced responses.
- Analysis of FRS2α localization and association with the plasma membrane.
Main Results:
- Palmitoylation at two specific sites is essential for stabilizing FRS2α's membrane association.
- Partial restoration of FGF1-induced MAPK activation and cellular responses occurred with single palmitoylation site mutants.
- Full restoration of signaling strength and FGF1-induced cellular activities required palmitoylation at both sites.
- FGF1-induced neuronal differentiation in PC12 cells strictly depends on FRS2α palmitoylation.
Conclusions:
- Dual palmitoylation of FRS2α is critical for robust signaling and membrane anchoring.
- FRS2α palmitoylation creates a platform for assembling signaling complexes involved in cytoskeletal reorganization.
- FGF1-induced neuronal differentiation is dependent on FRS2α palmitoylation, highlighting its specific role in this process.
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