Abstract
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. Different RTKs exhibit both basal and ligand-stimulated ubiquitination, linked to trafficking through different intracellular compartments including the secretory pathway, plasma membrane, endosomes and lysosomes. The ubiquitin ligase superfamily comprising the E1, E2 and E3 enzymes are increasingly implicated in this post-translational modification by adding mono- and polyubiquitin tags to RTKs. Conversely, removal of these ubiquitin tags by proteases called de-ubiquitinases (DUBs) enables RTK recycling for another round of ligand sensing and signal transduction. The endocytosis of basal and activated RTKs from the plasma membrane is closely linked to controlled proteolysis after trafficking and delivery to late endosomes and lysosomes. Proteolytic RTK fragments can also have the capacity to move to compartments such as the nucleus and regulate gene expression. Such mechanistic diversity now provides new opportunities for modulating RTK-regulated cellular responses in health and disease states.
Highlights
Receptor tyrosine kinases (RTKs) represent a family of integral membrane proteins exemplified in humans by 58 proteins divided into 20 subfamilies
The RTKs represent a diverse group of families that propagate signals derived from binding their cognate ligands via transduction along a milieu of intracellular signaling pathways
These circuits enable the sensing of changes in the extracellular environment and the translating of such information into appropriate cellular responses
Summary
Receptor tyrosine kinases (RTKs) represent a family of integral membrane proteins exemplified in humans by 58 proteins divided into 20 subfamilies. These include the epidermal growth factor receptor (ErbB), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and insulin-like receptor (IR) families [1,2,3] (Figure 1). ATP, resulting transfertyrosine of the γside phosphate onto autophosphorylation of the is an early and rate-determining step in controlling the flow ofan the hydroxyl group of a nearby tyrosine side chain. Early and rate-determining step in controlling the flow of information into different signaling circuits, suchin modifications are reversible via theImportantly, action of protein phosphatases (PTPs), whichvia which turn modulate cellular responses. The action of protein tyrosine phosphatases (PTPs), which enhances flexibility in controlling signaling output and cell function
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