The Epidermal Growth Factor Receptor (EGFR) is a Receptor Tyrosine Kinase that mediates cell proliferation and differentiation events during development and maintenance of complex organisms. Formation of specific, ligand-dependent EGFR dimers is a key step in stimulating EGFR signaling, and crystal structures of active, dimeric forms of isolated EGFR extracellular regions and kinase domains have revealed much about how dimer interactions regulate EGFR activity. The nature and role of the transmembrane region in regulating EGFR activity remains less clear, however. Proposed roles for the transmembrane region range from nonspecific but energetically favorable interactions to specific transmembrane dimer conformations being associated with active, inactive, or activity-modulated states of EGFR. To investigate the role of specific transmembrane dimers in modulating EGFR activity we generated thirteen EGFR variants with altered transmembrane sequences designed to favor or disfavor specific types of transmembrane region interactions. We show using FRET microscopy that EGFR transmembrane regions have an intrinsic propensity to associate in mammalian cell membranes that is counteracted by the extracellular region. We show using cell-based assays that each of the EGFR transmembrane variants except the Neu variant, which results in constitutive receptor phosphorylation, is able to autophosphorylate and stimulate phosphorylation of downstream effectors Erk and Akt. Our results indicate that many transmembrane sequences, including polyleucine, are compatible with EGFR activity and provide no evidence for specific transmembrane dimers regulating EGFR function.
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Phototrophs in the Blastochloris genus, known for growth using extremely long wavelength light in the near-infrared, assemble their photosystems with an additional subunit (yellow). The paper by Namoon and colleagues demonstrates that this subunit was recruited to shift the absorbance of the pigment–protein complex from a region of the spectrum where light doesn’t reach the surface of Earth, to longer wavelengths where photons are of even lower energy but are more abundant. Read more from Canniffe and colleagues in The role of the γ subunit in the photosystem of the lowest-energy phototrophs on pp 2449-2463.
Activity of EGFR transmembrane region variants indicates specific transmembrane dimers are not required for EGFR activity
Foteini Bartzoka, Monica Gonzalez-Magaldi, Patrick O. Byrne, Nicole I. Callery, Kalina Hristova, Daniel J. Leahy; Activity of EGFR transmembrane region variants indicates specific transmembrane dimers are not required for EGFR activity. Biochem J 22 December 2022; 479 (24): 2465–2475. doi: https://doi.org/10.1042/BCJ20220472
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