Abstract
Receptor tyrosine kinases (RTKs) are membrane proteins that control the flow of information through signal transduction pathways, impacting on different aspects of cell function. RTKs are characterized by a ligand-binding ectodomain, a single transmembrane α-helix, a cytosolic region comprising juxtamembrane and kinase domains followed by a flexible C-terminal tail. Somatic and germline RTK mutations can induce aberrant signal transduction to give rise to cardiovascular, developmental and oncogenic abnormalities. RTK overexpression occurs in certain cancers, correlating signal strength and disease incidence. Diverse RTK activation and signal transduction mechanisms are employed by cells during commitment to health or disease. Small molecule inhibitors are one means to target RTK function in disease initiation and progression. This review considers RTK structure, activation, and signal transduction and evaluates biological relevance to therapeutics and clinical outcomes.
Highlights
Receptor tyrosine kinases (RTKs) are membrane glycoproteins that regulate many cellular processes including cell migration, organ development, cell proliferation and differentiation
This review evaluates the structural differences between distinct RTKs through assessment of specific models, as well as the implications for signal transduction, cell function and disease
To prevent spontaneous trans-autophosphorylation, RTKs contain a number of auto-inhibitory elements, with most tyrosine kinase domain (TKD) inhibited in a unique way [37]
Summary
Receptor tyrosine kinases (RTKs) are membrane glycoproteins that regulate many cellular processes including cell migration, organ development, cell proliferation and differentiation. The seminal study by Cohen et al in 1965 [1] postulated that a membrane receptor was responsible for the proliferative response of epithelial cells to a soluble ligand, namely epidermal growth factor (EGF). In the mid-1980’s, two different groups elucidated the primary sequence of this membrane receptor that was called epidermal growth factor receptor or EGFR [2,3], triggering intensive research on these and other RTKs over the past 3 decades. This review evaluates the structural differences between distinct RTKs through assessment of specific models, as well as the implications for signal transduction, cell function and disease
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