Figure 2

Protein tyrosine kinase signaling pathways are potential targets in lymphatic endothelial cells. Protein tyrosine kinases are a diverse group of proteins that act in different subcellular compartments of the cell. Outlined in the diagram are some examples of the types of signaling pathways involving tyrosine kinases: a) Receptor tyrosine kinases are expressed on the cell surface and bind their specific ligands. Ligand binding activates the intrinsic protein tyrosine kinase domain and triggers the signaling cascade. (For example VEGFR-3 signalling). b) Non-PTK cell surface receptors can be associated with cytoplasmic tyrosine kinases. The cytoplasmic tyrosine kinase may be brought into contact with the receptor by direct binding, an example of which is the JAK kinases. Alternatively, the PTK may be tethered to the plasma membrane allowing it to rapidly interact with the activated receptor. The Src family kinases act in this manner. c) Other cytosolic PTKs act downstream in the signaling pathway or more broadly throughout the cell. The c-Abl kinase is an example of a PTK with activity in various subcellular locations. d) In some circumstances, the intracellular domain of a receptor tyrosine kinase may be cleaved and translocate to the nucleus where it is able to phosphorylate different targets. (For example ErbB4 can signal in this manner). e) Nuclear associated tyrosine kinases are localized to the nucleus; their activity may be modulated in response to signaling pathways. (An example of this is the fyn-related kinase). The types of inhibitors that could be used to target each tyrosine kinase pathway are listed on the right of the figure.