Receptor tyrosine kinases: mechanisms of activation and signaling
Introduction
Tyrosine phosphorylation is a highly regulated post-translational modification that is essential for inter- and intracellular communication in metazoans. The enzymes that catalyze phosphoryl transfer to tyrosine residues in protein substrates, using ATP as a phosphate donor, are the protein tyrosine kinases, of which there are 58 receptor types (RTKs) and 32 non-receptor types in the human genome [1]. The RTK family includes, among others, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors, fibroblast growth factor receptors (FGFRs), vascular endothelial growth factor receptors, Met (hepatocyte growth factor/scatter factor [HGF/SF] receptor), Ephs (ephrin receptors), and the insulin receptor. RTKs are essential components of cellular signaling pathways that are active during embryonic development and adult homeostasis. Because of their roles as growth factor receptors, many RTKs have been implicated in the onset or progression of various cancers, either through receptor gain-of-function mutations or through receptor/ligand overexpression [2].
RTKs are single-pass, type I receptors resident in the plasma membrane. Generally, RTKs are activated through ligand-induced oligomerization, typically dimerization, which juxtaposes the cytoplasmic tyrosine kinase domains [3]. For most RTKs, this juxtaposition facilitates autophosphorylation in trans of tyrosine residues in the kinase activation loop or juxtamembrane region, inducing conformational changes that serve to stabilize the active state of the kinase [4]. These and other phosphotyrosine residues serve as recruitment sites for a host of downstream signaling proteins — enzymes and adapter/scaffolding proteins — typically through Src homology-2 (SH2) or phosphotyrosine-binding (PTB) domains, which recognize phosphotyrosine residues in specific sequence contexts [5].
Understanding the precise structural mechanisms by which ligands and co-factors induce RTK oligomerization and activation continues to be an active area of research. In addition, advances in proteomics techniques and live-cell imaging have yielded global spatial and temporal views of cellular signal propagation. This review highlights the recent advances in these areas.
Section snippets
Mechanisms of activation of receptor tyrosine kinases
Several years ago, the structural mechanisms by which members of the EGFR subfamily of RTKs (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4) undergo ligand-induced dimerization (2:2 ligand–receptor complex) were elucidated through crystallographic studies [6]. Despite these major advances, questions regarding the kinetics of ligand-receptor and receptor-receptor association at the cell surface remained. For example, there is evidence that EGFRs can exist in a ligand-free, pre-dimerized (but inactive) state
Signaling mechanisms downstream of activated receptor tyrosine kinases
In most cases, the phosphotyrosine recruitment sites in RTKs are located in the C-terminal tail of the receptor, the juxtamembrane region, or the kinase insert region. These regions in RTKs are, for the most part, unstructured and are readily accessible to SH2 and PTB domains. In contrast, the phosphorylated activation loop within the insulin receptor kinase domain (IRK) has been shown to be the target for the SH2 domain-containing adapter proteins APS and Grb10/14. The IRK activation loop
Global studies of receptor tyrosine kinase signaling
Studies of RTK signaling pathways have begun to move from detailed studies of individual components to system-wide analyses of entire cascades. These advances have been made possible by the development of new technologies in proteomics and functional genomics. Several recent studies have provided ‘panoramic’ views of tyrosine phosphorylation events that would have been unthinkable a few years ago.
Quantitative proteomic strategies have enabled the unbiased analysis of the temporal aspects of
Conclusions
Because of their key roles in mediating cellular proliferation, RTKs, as well as non-receptor tyrosine kinases such as Src and Abl, are attractive candidates for therapeutic intervention. Over the past 15 years, much has been learned regarding the regulatory mechanisms that govern RTK expression, ligand activation, downstream signaling and downregulation. This fundamental biochemical information has been crucial in the quest to develop targeted therapeutics, both to the extracellular regions of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
Due to space limitations, we regret that we were not able to highlight all of the recent relevant studies on RTK signaling mechanisms. Research support is acknowledged from the National Institutes of Health (DK052916 and NS053414 to SRH; CA058530 to WTM).
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