The first growth factors identified and studied during the early 1970s were Epidermal Growth Factor (EGF) and Nerve Growth Factor (NGF). It was soon demonstrated that EGF and NGF mediate their cellular and physiological effects by binding to specific cell membrane receptors: the EGF receptor (EGFR) and the NGF receptor (NGFR), respectively. The mechanisms of activation and signaling of these receptors were compared to those of insulin and IGF1, which bind and activate the Insulin Receptor (IR) and IGF1 Receptor (IGF1R). These comparisons gained further significance with the discovery that EGFR, NGFR, IR, IGF1R, and many other membrane receptors belong to the receptor tyrosine kinase (RTK) family of cell signaling molecules. Early insights into the activation and signaling mechanisms of EGFR revealed that ligand binding to its extracellular domain induces and stabilizes the formation of EGFR dimers. This dimerization plays a critical role in activating the receptor's intrinsic tyrosine kinase activity. Through an intermolecular process, this activation leads to the autophosphorylation of multiple tyrosine residues in the C-terminal tail of EGFR. The cytoplasmic domain of EGFR serves not only as an enzyme that phosphorylates various substrates but also as a scaffold that recruits and regulates multiple signaling proteins through complex formation. While different ligands induce RTK dimerization and activation through variations on a shared theme, this paradigm is universal among all RTKs and is similarly observed in the activation of other surface receptors. Further important discoveries regarding the mode of action of EGFR and other RTKs made during the 1970s and 1980s include the following: Signaling Modules: Molecules containing SH2, SH3, and other small protein modules were found to play key roles in mediating cellular activities downstream of RTKs and many other signaling molecules. Ligand-Dependent Endocytosis: Ligand binding to the extracellular domain of RTKs stimulates receptor-mediated endocytosis and intracellular trafficking ,which are essential for proper signal transduction. Oncogenic Mutations: A variety of gain-of-function oncogenic mutations were identified in EGFR and other RTKs. These mutations were shown to be critical drivers of many human cancers. These early discoveries, along with others made during the 1980s, laid the conceptual groundwork for the development of targeted therapies. They paved the way for the discovery and clinical application of more than 50 targeted small-molecule cancer drugs and therapeutic antibodies, which have significantly improved patient outcomes in oncology.

Joseph Schlessinger | Discovering how receptor tyrosine kinases are activated and signals

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