Conclusion

Despite the importance of RTK signal transduction cascades in microvessel development and function, it is clear that there are large gaps in our understanding of these cascades in microvascular cells for each of the RTKs reviewed. A more comprehensive knowledge of events at the receptor, downstream pathways, and linkage with effector mechanisms is needed for each of the microvascular RTKs. Important questions also remain on the specificity of signaling cascades in the microvasculature, how different RTKs can activate the same signaling pathway but have different effects on the cell. For example, VEGF and Angl both activate the Akt pathway, but VEGF stimulates proinflammatory gene expression and Angl suppresses this via a mechanism that requires Akt activation. Differences in spatial, temporal, and quantitative aspects of signal cascades as well as the profile of signaling events elicited by each receptor is likely to underlie some of the specificity in signaling. The cell is required to integrate many signals into the physiological setting. An important challenge is to understand how the different RTK signaling pathways coordinate, both with each other and with non-RTK pathways. Such coordination is likely to involve interactions between cascades within the cell as well as regulation at the level of ligand and receptor. For example, VEGF impacts Tie signaling by inducing proteolytic cleavage of Tiel, and hetero-oligomeric complexes of VEGFR1:VEGFR2 and Tie1:Tie2 provide mechanisms for cross-talk between receptors of the same family. The specialized functions and architecture of the microvasculature provide an opportunity to gain fundamental insights into mechanisms of signal transduction and how they regulate tissue morphogenesis and maintenance. Such insights may provide new strategies for treatment of ischemic disease, cancer, and inflammatory conditions.

Glossary

Adaptor protein: (also called adapter protein): A protein that can act as a binding intermediate. Adaptor proteins bind to one protein, for example an activated receptor, and provide binding sites for the recruitment of other proteins.

Autophosphorylation: The phosphorylation of a protein by itself. Receptor tyrosine kinases are said to undergo autophopshorylation following ligand activation. In fact, ligand binding enhances RTK dimerization or oligomerization, allowing individual RTKs within the complex to be phos-phorylated by other RTKs also in the complex (transphosphorylation).

PTB domain: Phosphotyrosine binding domains are between 100 and 170 amino acids and bind phosphotyrosine, usually flanked by an asparagines-proline-X amino peptide. PTB domains in some proteins appear to have broader binding specificity, including nonphosphorylated sequences.

SH2 domain: SH2 domains comprise approximately 100 amino acids and bind phosphotyrosine-containing peptides. The specificity of SH2 binding is determined by the amino acid residues flanking the phosphory-lated tyrosine.

SH3 domain: A protein module binding proline-rich peptides.

Further Reading

Autiero, M., Waltenberger, J., Communi, D., Kranz, A., Moons, L., Lambrechts, D., Kroll, J., Plaisance, S., De Mol, M., Bono, F., et al. (2003). Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Fltl and Flkl. Nat. Med. 9, 936-943. Cheng, N., Brantley, D. M., and Chen, J. (2002). The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 13, 75-85. Claesson-Welsh, L. (2003). Signal transduction by vascular endothelial growth factor receptors. Biochem. Soc. Trans. 31, 20-24. An excellent, concise review of the key features of VEGF-receptor signaling. Cross, M. J., Lu, L., Magnusson, P., Nyqvist, D., Holmqvist, K., Welsh, M., and Claesson-Welsh, L. (2002). The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells. Mol. Biol. Cell 13, 2881-2893.

Jones, N., Iljin, K., Dumont, D. J., and Alitalo, K. (2001). Tie receptors: New modulators of angiogenic and lymphangiogenic responses. Nat. Rev. Mol. Cell. Biol. 2, 257-267. A very good summary of the Tie receptor biology and signaling, concentrating on roles in angiogenesis. Master, Z., Jones, N., Tran, J., Jones, J., Kerbel, R. S., and Dumont, D. J. (2001). Dok-R plays a pivotal role in angiopoietin-1 -dependent cell migration through recruitment and activation of Pak. EMBO J. 20, 5919-5928.

Nagashima, K., Endo, A., Ogita, H., Kawana, A., Yamagishi, A., Kitabatake, A., Matsuda, M., and Mochizuki, N. (2002). Adaptor protein Crk is required for Ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Mol. Biol. Cell. 13, 4231-4242. A research article illustrating some of the approaches used for delineating intracellular signaling pathways activated by receptor tyrosine kinases. Zachary, I., and Gliki, G. (2001). Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res. 49, 568-581. This article is valuable in linking the signaling events elicited by VEGF to downstream functional effects of the growth factor.

Capsule Biography

Marie Marron and Nick Brindle work on receptor tyrosine kinase signaling with particular focus on RTKs in vascular formation, regression, and maintenance. They are supported mainly by the British Heart Foundation and Wellcome Trust.

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