Receptor tyrosine kinases: legacy of the first two decades

Abstract

Receptor tyrosine kinases (RTKs) and their cellular signaling pathways play important roles in normal development and homeostasis. Aberrations in their activation or signaling leads to many pathologies, especially cancers, motivating the development of a variety of drugs that block RTK signaling that have been successfully applied for the treatment of many cancers. As the current field of RTKs and their signaling pathways are covered by a very large amount of literature, spread over half a century, I am focusing the scope of this review on seminal discoveries made before tyrosine phosphorylation was discovered, and on the early days of research into RTKs and their cellular signaling pathways. I review the history of the early days of research in the field of RTKs. I emphasize key early findings, which provided conceptual frameworks for addressing the questions of how RTKs are activated and how they regulate intracellular signaling pathways.

Figure 1.

A time line of key findings during the history of RTKs, with emphasis on findings and discoveries that produced the conceptual framework in the development of the RTK field and its application for cancer therapy. References for the key findings are also presented in the text (Lee et al. 1985; Libermann et al. 1985; Margolis et al. 1990; Bottaro et al. 1991; Bae et al. 2009).

Figure 2.

Two contrasting views during the early days for how EGF binding to the extracellular region of EGFR stimulates the tyrosine kinase domain in the cytoplasm. (A) An “intramolecular” mechanism. Ligand-stimulated EGFR monomers transmit a conformational change through the transmembrane helix to activate the tyrosine kinase domain and mediate autophosphorylation by an intramolecular process. (B) An “intermolecular” mechanism. Ligand binding stimulates lateral contacts between a pair of EGFR molecules, resulting in EGFR dimerization mediated by interactions between extracellular regions, transmembrane domains, and cytoplasmic regions resulting in stimulation of tyrosine kinase activity and autophosphorylation by an intermolecular process.

Figure 3.

Models for ligand stimulation of RTK dimerization and activation. The scheme presented in (A) is based on data from Yarden and Schlessinger (1987) with minor modifications. The scheme presented in (B) is based on data presented in Schlessinger et al. (2000). This is a generalized allosteric/dimerization model for RTK activation that applies equally to EGFR and insulin receptor. Full details are presented in the body of the article.