Cell Signaling by Receptor Tyrosine Kinases

A large group of genes in all eukaryotes encode for proteins that function as membrane spanning cell surface receptors. Membrane receptors can be classified into distinct families based upon the ligands they recognize, the biological responses they induce and, more recently, according to their primary structures. A great variety of ligands bind to and regulate the activity of cell surface receptors, including small organic molecules, lipids, carbohydrates, peptides, and proteins. One large family of cell surface receptors is endowed with intrinsic protein tyrosine kinase activity. These receptor tyrosine kinases (RTKs) catalyze transfer of the γ phosphate of ATP to hydroxyl groups of tyrosines on target proteins (Hunter 1998). RTKs play an important role in the control of most fundamental cellular processes including the cell cycle, cell migration, cell metabolism and survival, as well as cell proliferation and differentiation. All receptor tyrosine kinases contain an extracellular ligand binding domain that is usually glycosylated. The ligand binding domain is connected to the cytoplasmic domain by a single transmembrane helix. The cytoplasmic domain contains a conserved protein tyrosine kinase (PTK) core and additional regulatory sequences that are subjected to autophosphorylation and phosphorylation by heterologous protein kinases (Hunter 1998; Hubbard et al. 1998). Lymphokines such as erythropoietin and interferon also mediate their responses by tyrosine phosphorylation. However, rather than containing an intrinsic protein tyrosine kinase activity, the relatively short cytoplasmic domains of these receptors interact through noncovalent interactions with members of the Jak family of nonreceptor tyrosine kinases (Darnell et al. 1994; Ihle 1995). Apart from the lack of covalent linkage to a kinase, the mechanism of activation of these binary receptors largely resembles that of receptor tyrosine kinases (Lemmon and Schlessinger 1994; Heldin 1995; Jiang and Hunter 1999). The purpose of this review is to describe general concepts underlying the mechanism of action of RTKs and the signaling pathways that they regulate, while attempting to shed light on the question of how specificity is defined by the action of RTKs, and how a specific biological response can be generated by the diverse array of signaling pathways activated by all RTKs.