Signaling by Growth Factor Receptors.

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 (1,2). 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 (3). A variety of cellular proteins are phosphorylated by the activated kinase, including the receptors themselves (4). 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 (5). [ABSTRACT FROM AUTHOR]