Alternative dimerization of receptor tyrosine kinases with signal transduction through a cellular membrane

Abstract

Receptor tyrosine kinases (RTKs) occupy a separate functional niche among membrane receptors, which is determined by the special features of mechanisms of the signal transduction through a cellular membrane. RTKs are involved in the regulation of development and homeostasis of all the tissues of a human organism, playing a central role in cell proliferation, differentiation, and adhesion. A necessary condition of the biochemical signal transduction through a plasmatic membrane is a ligand-dependent or a ligand-independent dimerization (and/or an oligomerization) of RTKs which is accompanied by conformational rearrangements of all the RTK domains, including the α-helical transmembrane segments. In this review, the main aspects of structure-function relationship for RTKs from various receptor subfamilies are briefly discussed. It is shown in the light of the recently obtained biophysical and biochemical data that functioning of RTK receptors is mediated not only by protein–protein interactions, but by the state of the lipid environment as one of the main components of a self-consistent signal transduction system as well. The new principles of intercellular signal transduction through a membrane replenish the molecular mechanisms of the RTK functioning that have been earlier proposed and explain a number of paradoxes which are observed upon activation of wild-type receptors and the receptors with pathogenic transmembrane mutations. Understanding of the complex mechanisms of the signaling processes can facilitate the successful search for new opportunities of influence on the RTK biological functions with potential therapeutic consequences.