References:
- Inder, K., Harding, A., Plowman, S.J., Philips, M.R., Parton, R.G. and Hancock, J.F. (2008) Activation of the MAPK module from different spatial locations generates distinct systems outputs. Mol Biol Cell. 11: 4776-84.
- Plowman, S.J.,* Shalom-Feuerstein, R.*, Roblat, B., Ariotti, N., Tianhai, T., Hancock, J.F. and Kloog, Y. (2008) K-Ras nanocluster formation and function is regulated through interaction with the putative prenyl-binding pocket of Galectin-3. Cancer Res. 68: 6608-6616.
- Plowman, S. J., Ariotti, N., Goodall, A., Parton, R.G. and Hancock, J.F. (2008) Electrostatic interactions positively regulate K-Ras nanocluster formation. Mol Cell Biol.28; 4377-4385.
- Abankwa, D., Hanzal-Bayer, M., Ariotti, N., Plowman, S. J., Gorfe, A. A., Parton, R. G., McCammon, A. and Hancock, J.F. (2008) A novel switch region regulates H-ras membrane orientation and signal output. EMBO J. 27; 727-735.
- Plowman, S. J.*, Belanis, L.*, Rotblat, B., Hancock, J.F. and Kloog, Y. (2008) Galectin-1 is a novel structural component and a major regulator of H-Ras nanoclusters. Mol Biol Cell. 19; 1404-1414
- Tian, T., Harding, A., Inder, K., Plowman, S. J., Parton, R. G. and Hancock J. F. (2007). Plasma membrane nano-switches generate high-fidelity Ras signal transduction. Nat Cell Biol 9: 905-14.
- Plowman, S. J., Muncke, C., Parton, R. G. and Hancock, J. F. (2005) H-ras, K-ras and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. PNAS USA 102: 15500-15505.
- Plowman, S. J. and Hancock, J.F. (2005) Ras signalling from plasma membrane and endomembrane microdomains. Biochim Biophys Acta. 1746: 274-283.
Sarah Plowman, Ph.D.
Assistant Professor
UTHSC-H Medical School, 713-500-7056
Sarah.J.Plowman@uth.tmc.edu
Receptor tyrosine kinases, nano-organization and signal transduction
The development, growth and homeostasis of multi-cellular organisms are regulated by the interaction of growth factors with cell surface receptors such as receptor tyrosine kinases (RTK). One class of RTK is the epidermal growth factor receptor (EGFR) family, which is composed of four members, EGFR (ErbB), ErbB2 (Her2), ErbB3 and ErbB4. These cell surface receptors are single transmembrane domain proteins, which have intrinsic tyrosine kinase activity. Growth factor binding to a receptor leads to receptor activation and autophosphorylation of a number of tyrosine residues in the C-terminus of the receptor. These phosphorylated tyrosine residues act as binding sites for a number of adapter and effector proteins, which regulate the activation of downstream signaling cascades such as the Ras/Raf/MEK/ERK pathway. Over-expression, truncation mutations and mutations in the kinase domain, that lead to constitutive activation of the receptor, are associated with the development of cancer.
The plasma membrane is composed of many different lipid species. This heterogeneity leads to the formation of different types of lipid domains that either exclude or include membrane proteins. Therefore it has been hypothesized that the spatial segregation of membrane proteins plays an important role in the regulation of signal transduction. The goal of my research program is to elucidate how spatial organization on the plasma membrane regulates the function of receptor tyrosine kinases, using EGFR as a model. In particular, we are currently investigating how EGFR activation drives the formation of autonomous signaling domains by the production of second messenger lipid species. By using biochemistry, molecular biology, fluorescence and electron microscopy to investigate the functional consequences of receptor organization, my research will yield important insights into the role of compartmentalized receptor signaling in normal and cancerous cells.
