Fyn and TOM1L1 are recruited to clathrin-coated pits and regulate Akt signaling

Area of Science:

• Cell Biology
• Molecular Signaling
• Receptor Trafficking

Background:

• Epidermal growth factor receptor (EGFR) signaling pathways regulate fundamental cell processes.
• EGFR activation leads to phosphatidylinositol-3-kinase/Akt pathway activation and receptor endocytosis via clathrin-coated pits (CCPs).
• Previous studies indicated clathrin's role in EGF-stimulated Akt activation, independent of receptor endocytosis.

Purpose of the Study:

• To investigate the specific mechanisms by which clathrin-coated pits (CCPs) control epidermal growth factor receptor (EGFR) signaling.
• To identify key molecular players within CCPs that mediate EGFR-induced Akt activation.

Main Methods:

• Utilized techniques to analyze protein enrichment and function within specific CCP subsets.
• Investigated the roles of TOM1L1 and Fyn in EGFR signaling pathways.
• Examined the impact of TOM1L1 and Fyn perturbations on Akt phosphorylation (Akt1 and Akt2).

Main Results:

• A subset of CCPs was identified with unique protein compositions and lifetimes, enriched in TOM1L1 and Fyn.
• Perturbation of TOM1L1 or Fyn selectively impaired EGF-stimulated Akt2 phosphorylation, but not Akt1.
• EGF stimulation induced the recruitment of SHIP2 to CCPs in a TOM1L1- and Fyn-dependent manner.

Conclusions:

• The recruitment of TOM1L1 and Fyn to specific CCPs is essential for supporting EGFR signaling.
• These CCP-associated proteins play a critical role in the regulation of Akt activation downstream of EGFR.
• CCPs act as signaling platforms that modulate the amplitude and specificity of EGFR responses.