ИСТИНА

Receptor tyrosine kinases (RTKs) play a central role in biochemical signal transduction across the membrane and involved in coordination of various cellular processes requiring intercellular communication. During signal transduction across plasma membrane, RTKs are activated by proper ligand-induced dimerization or by reorientation of monomers in preformed receptor dimer upon ligand binding. Specific helix-helix interactions of transmembrane domains (TMD) are believed to be important for RTK lateral dimerization and signal transduction. The observed RTK TMD packing diversity appears in favor of the lipid-mediated rotation-coupled activation mechanism recently proposed by us, which implies that the sequence of structural rearrangements of RTK domains is associated with perturbations of the lipid bilayer in the course of ligand-induced receptor activation, considering the receptor together with its lipid environment as a self-consistent signal transduction system. The human epidermal growth factor receptors (HER) and the fibroblast growth factor receptors (FGFR) families serves as excellent model RTK to illustrate how ligandinduced conformational rearrangements and specific dimerization of extracellular domains lead to the allosteric activation of the cytoplasmic kinase domains, resulting in signal propagation across the membrane. Besides, HER and FGFR relatives are known oncogenic drivers in many cancers, and inhibitors of these receptors have been among the most successful examples of targeted cancer therapies to date. Pathogenic transmembrane mutations found for the HER and FGFR relatives are located as a rule in narrow “hot-spot” regions within the specific TMD helix-helix interfaces assuming that the intermolecular interactions inside membrane are important for the RTK cell signaling dysfunction in human organism. The work is supported by Russian Science Foundation (project #14-50-00131).