Regulation of Receptor Tyrosine Kinase Ligand Processing

Abstract

A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.C ells must talk to one another. This principle applies throughout the tree of life: from unicellular bacteria, to the trillions of cells that coordinate to make a mammal. Communication between cells requires dedicated machinery, capable of relaying information across membranes. Transmembrane proteins are therefore essential for signaling. Understanding how this is regulated is paramount. In mammals, receptor tyrosine kinases (RTKs) and their ligands are important examples of such machinery (Schlessinger 2000), controlling many biological processes including development, immunity, tissue repair, and metabolic homeostasis (Ullrich and Schlessinger 1990). They are transmembrane proteins with an extracellular ligand-binding motif and an intracellular kinase domain. As discussed in other chapters, a common mode of RTK activation involves receptor dimerization induced by ligand binding (Lemmon and Schlessinger 2010).Regulated access of ligand to receptor, over distance and time, is key to controlling signaling. Ligands are frequently synthesized as transmembrane forms; when they remain membrane-tethered and cannot diffuse, the range over which they can operate is limited to adjacent cells (Massague and Pandiella 1993; Singh and 1 Present address: Instituto

The EGFR Family: Not So Prototypical Receptor Tyrosine Kinases

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Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases

“…Generally, upon ligand binding, RTKs undergo multiple proteolytic cleavages in a protease‐dependent manner . For example, members of at least ten RTK sub‐families undergo a series of secretase cleavages after activation to remove the extracellular domain followed by release of the intracellular domain from the cell membrane, a process that is also known as regulated intra‐membrane proteolysis .…”

The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans

“…EGF family ligands are initially produced as transmembrane precursors, but proteolysis by ADAM-17 or Rhomboidfamily proteases typically occurs in the juxtamembrane region to release the active EGF peptide for paracrine signaling (Sahin et al 2004;Adrain and Freeman 2014). The different splice isoforms of C. elegans LIN-3/EGF differ in the region that would be expected to confer protease specificity, so the different biological activities observed for these isoforms might reflect different availabilities of isoform-specific proteases.…”

“…LIN-3 is the only EGFrelated ligand in C. elegans, but alternative splicing generates at least four LIN-3 protein isoforms (S, L, XL, and XXL) that differ in their extracellular juxtamembrane domains ( Figure 4, A and B) (Dutt et al 2004;Van Buskirk and Sternberg 2007;Gerstein et al 2010). These isoforms may differ in binding partners or in susceptibility to proteolytic cleavage (Dutt et al 2004), which typically releases the active EGF domain from the transmembrane precursor (Rose-John 2013; Adrain and Freeman 2014). Prior OE studies have revealed some functional differences among these LIN-3 isoforms (Dutt et al 2004;Van Buskirk and Sternberg 2007), but their individual expression patterns and requirements are not known.…”