Signaling by growth factor receptors.

Abstract

Growth factor receptors (GFRs) represent a subset of a large class of proteins that serve as extracellular environment sensors of the cell. They are single transmembrane proteins with an extracellular ligand-binding domain (LBD) and an intracellular tyrosine kinase domain (,). Individual GFRs are expressed in specific cell types and their expression is highly regulated during development. In the case of polarized cells, newly synthesized receptors are targeted to specific faces of the cell through the exocytic pathway. The mechanism of signal transduction by ligand-activated GFRs is schematically depicted in Fig. 1. Oligomerization induced by ligand binding results in the allosteric activation of the intracellular tyrosine kinase (). A variety of cellular proteins are phosphorylated by the activated kinase, including the receptors themselves (). The phosphorylated tyrosine residues serve as docking sites for various signal transducers containing a phosphotyrosine-binding domain or an Src homology 2 (SH2) domain. Thus, a multiprotein signaling complex is assembled in the vicinity of the receptor. The ligand determines which receptors are activated, whereas the receptors involved dictate the type of proteins recruited to the signaling complex, which in turn determines the nature of the downstream signaling cascade. Although a large number of GFR families have been identified, their mode of activation, orchestration of signaling, and downregulation are modular (). Open image in new window Fig. 1. Schematic representation of receptor activation and downregulation. Ligand-induced dimerization leads to auto- and transphosphorylation of tyrosine residues in the C-terminus of the receptor, which serve as docking sites for cytoplasmic proteins containing a phosphotyrosine binding domain. Note that some of the recruited proteins also serve as substrates of the receptor. Only a few of the pathways activated by the receptor are depicted here. Many downstream effectors are subsequently activated, and the signal is carried across the nuclear membrane, culminating in nascent gene expression and cell-fate determination. The c-Cbl•E2 complex may interact with the receptor already at the cell surface, and it mediates receptor ubiquitination. Ubiquitinated receptors are then sorted into clathrin-coated pits and endocytosed. The fate of the receptor in the early endosome may be determined by the extent of ubiquitination: de-ubiquitinated receptors may be recycled back to the plasma membrane while extensively ubiquitinated receptors are apparently carried to multivesicular bodies and eventually to the lysosome, where they are degraded.