Regulation and targets of receptor tyrosine kinases.

Ligand-mediated activation of receptor tyrosine kinases (RTKs) results in autophosphorylation of both the receptor catalytic domain and noncatalytic regions of the cytoplasmic domain. Catalytic domain phosphorylation leads to activation and potentiation of receptor kinase activity. Noncatalytic domain phosphorylation creates docking sites for downstream cytoplasmic targets, which bind to specific receptor phosphotyrosine residues. Downstream signaling pathways are constructed in a modular fashion. In addition to SH2 and PTB (phosphotyrosine binding) domains, downstream signal proteins also contain domains that recognize other protein and phospholipid motifs. The arrangement and re-arrangement of various combinations of modular domains in different signaling proteins (combinatorial use) has allowed for the creation of complex signaling networks and pathways. In addition to performing catalytic functions, signaling proteins serve as scaffolds for the assembly of multiprotein signaling complexes, as adaptors, as transcription factors and as signal pathway regulators. Recent results show that the juxtamembrane region of Eph receptors is important in receptor autoregulation. Mutations in the juxtamembrane region of several RTKs have been shown to play a role in oncogenesis. It is likely that dysregulation of other modular components of signaling pathways also plays a role in oncogenic transformation.