ABSTRACT
Tyrosine kinases and cancer Cell signaling by receptor tyrosine kinases Tyrosine phosphorylation is a central mechanism for controlling cell signaling leading to proliferation, migration, and differentiation. The enzyme families that control tyrosine phosphorylation are the tyrosine kinases and the protein tyrosine phosphatases. The human genome encodes approximately 90 tyrosine kinases (Figure 11.1). These are further divided into the receptor tyrosine kinases (RTKs) and the cytosolic tyrosine kinases. Most RTKs transmit signals from soluble growth factors, whereas the soluble tyrosine kinases in most cases act as components of intracellular pathways activated by RTKs or other cell surface proteins. The RTKs contain an extracellular ligand-binding domain, which is connected to the cytoplasmatic intracellular domain by a single transmembrane helix. With the exception of the insulin receptor subfamily, RTKs occur as monomers in the absence of ligand. Activation of RTKs is now well characterized, and involves multiple steps (Figure 11.2). Activation is triggered by ligand binding to the extracellular domain, which induces dimerization of the receptors. Dimerization leads to autophosphorylation of regulatory tyrosines and kinase activation. The phosphorylated receptor is then able to recruit and activate intracellular signaling enzymes, which initiates signaling events that lead to alteration in gene transcription and ultimately to cellular responses such as proliferation or migration.
