Receptor tyrosine kinases (RTKs) have essential roles in the formation, maintenance, and function of the microvasculature. Vasculogenesis and angiogenesis, involving differentiation, migration, proliferation, and survival of endothelial cells, as well as microvascular regression, inflammation, and permeability are all controlled by RTK signaling pathways. Being able to understand how these pathways work will provide new opportunities for therapeutic manipulation of the microvasculature relevant to a wide range of diseases, from inflammatory diseases to tumor growth and tissue ischemia. In this chapter, signaling pathways utilized by four of the key families of RTKs of the microvasculature are outlined. Because of space constraints, we have focused on RTKs in the endothelium. Signaling pathways controlling the specialized functions of the microvasculature are best studied in the physiologically appropriate cell types. Although data from nonvascular cells can be extremely valuable in guiding understanding, such cells may lack key components of signaling or effector pathways, co-receptors, and signaling cross-talk important in the mechanisms by which the RTKs exert their effects in vascular cells. We have, therefore, focused on RTK signaling pathways demonstrated in endothelial cells rather than extrapolated from findings in nonvascular cells.
RTKs are activated by ligand-induced clustering. This permits transphosphorylation of regulatory tyrosine residues in the RTKs, activating kinase activity and inducing phosphorylation of additional tyrosine residues. These phospho-
tyrosines act as docking sites for SH2 and PTB domains in intracellular signaling molecules, leading to their recruitment to the RTKs. Such signaling molecules may then become activated by phosphorylation or protein-to-protein interactions and initiate a signaling cascade linking the RTK to effector mechanisms. In the following sections, these signaling cascades are reviewed with respect to the microvas-culature. Where amino acid numbers are given, they refer to positions in the human sequences.
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