It Takes More than Two to Tango: Complex, Hierarchal, and Membrane-Modulated Interactions in the Regulation of Receptor Tyrosine Kinases

Simple Summary Receptor tyrosine kinases probably constitute the most important subfamily of transmembrane receptors with respect to their role in regulating the balance between cell proliferation and cell death. Their activation involves ligand-induced conformational changes followed by their dimerization. Although this simple mechanism is still known to lie at the root of the process, the picture is complicated by the involvement of several receptor domains in the dimerization and the formation of larger receptor aggregates. Both clustering and activation are influenced by lipid-mediated interactions of the plasma membrane with the receptors. The intricate regulation of receptor activation is subverted in cancer that involves not only alterations in receptor structure and expression but also changes in lipid composition of the cell membrane. This paper provides a concise overview of how these biophysical aspects of transmembrane signaling regulate this important process in health and disease. The search for an understanding of how cell fate and motility are regulated is not a purely scientific undertaking, but it can also lead to rationally designed therapies against cancer. The discovery of tyrosine kinases about half a century ago, the subsequent characterization of certain transmembrane receptors harboring tyrosine kinase activity, and their connection to the development of human cancer ushered in a new age with the hope of finding a treatment for malignant diseases in the foreseeable future. However, painstaking efforts were required to uncover the principles of how these receptors with intrinsic tyrosine kinase activity are regulated. Developments in molecular and structural biology and biophysical approaches paved the way towards better understanding of these pathways. Discoveries in the past twenty years first resulted in the formulation of textbook dogmas, such as dimerization-driven receptor association, which were followed by fine-tuning the model. In this review, the role of molecular interactions taking place during the activation of receptor tyrosine kinases, with special attention to the epidermal growth factor receptor family, will be discussed. The fact that these receptors are anchored in the membrane provides ample opportunities for modulatory lipid-protein interactions that will be considered in detail in the second part of the manuscript. Although qualitative and quantitative alterations in lipids in cancer are not sufficient in their own right to drive the malignant transformation, they both contribute to tumor formation and also provide ways to treat cancer. The review will be concluded with a summary of these medical aspects of lipid-protein interactions.