HER2 expression defines unique requirements for flotillin and c-Src in EGFR signaling

Abousawan, John; Orofiamma, Laura; Fairn, Gregory D.; Antonescu, Costin N.

doi:10.1242/jcs.260133

Cited by 2 publications

(1 citation statement)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are two flo$llin homologs in mammalian cells, FLOT1 and FLOT2. They are involved in diverse physiological func$ons, including endocytosis [4][5][6] , signaling 7,8 , protein trafficking 8,9 and cytoskeleton remodeling 10,11,12 (reviewed in 13,14 ) . Flo$llin overexpression has also been implicated in cell invasion and metastasis during tumorigenesis 15,14 .…”

Section: Introduc-onmentioning

confidence: 99%

Molecular mechanism of the flotillin complex in membrane microdomain organization

Lu,

Qian,

et al. 2024

Preprint

View full text Add to dashboard Cite

Flotillin-1 and flotillin-2, initially identified as markers of lipid rafts, assemble together as hetero-oligomers and facilitate the organization of flotillin membrane microdomains, which play a crucial role in various cellular processes, such as endocytosis, protein sorting, and vesicle trafficking. However, the molecular mechanisms underlying flotillin oligomerization and flotillin microdomain organization remain incompletely understood. Here we present the cryo-electron microscopy structure of the human flotillin complex, at an overall resolution of 3.57 angstrom. It demonstrates that flotillin-1 and -2 are alternately arranged to form a 44-mer ring structure. This dome-shaped complex is hollow and sealed, attaching to the cytoplasmic leaflet of the plasma membrane and encompassing a circular domain with a diameter of approximately 30 nm. These structural features demonstrate a direct role for the flotillin complex in segregating the membrane to organize an isolated microdomain and also suggests a potential regulatory role in sequestering its interacting proteins. The cryo-electron tomography study further demonstrates the structural plasticity of the flotillin complexes in situ, indicative of dynamic conformational changes during their functional activities. In addition, aggregations of the flotillin complexes on the plasma membrane or intracellular vesicles, are frequently observed. Our data suggest that the flotillin complex constitutes the basic structural unit of membrane microdomains, and the further clustering of flotillin complexes might facilitate the formation of larger and more elaborate membrane microdomains. These findings enhance our understanding of the architecture of the SPFH family proteins and their common role in membrane microdomain organization, and more importantly, provide models for explaining the diverse functions of flotillin proteins in different biological processes.

show abstract

Section: Introduc-onmentioning

confidence: 99%

Molecular mechanism of the flotillin complex in membrane microdomain organization

Lu,

Qian,

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling

et al. 2023

Self Cite

View full text Add to dashboard Cite

The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology. EGFR is activated by ligand binding, triggering receptor dimerization, activation of kinase activity, and intracellular signaling. EGFR is transiently confined within various plasma membrane nanodomains, yet how this may contribute to regulation of EGFR ligand binding is poorly understood. To resolve how EGFR nanoscale compartmentalization gates ligand binding, we developed single-particle tracking methods to track the mobility of ligand-bound and total EGFR, in combination with modeling of EGFR ligand binding. In comparison to unliganded EGFR, ligand-bound EGFR is more confined and distinctly regulated by clathrin and tetraspanin nanodomains. Ligand binding to unliganded EGFR occurs preferentially in tetraspanin nanodomains, and disruption of tetraspanin nanodomains impairs EGFR ligand binding and alters the conformation of the receptor’s ectodomain. We thus reveal a mechanism by which EGFR confinement within tetraspanin nanodomains regulates receptor signaling at the level of ligand binding.

show abstract

HER2 expression defines unique requirements for flotillin and c-Src in EGFR signaling

Cited by 2 publications

References 92 publications

Molecular mechanism of the flotillin complex in membrane microdomain organization

Molecular mechanism of the flotillin complex in membrane microdomain organization

Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling

Contact Info

Product

Resources

About