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Pseudopod Activity and Substrate Attachment in Nerve Growth Cones and Migrating Cancer Cells
The primary focus of the laboratory's research is the regulation of pseudopod activity and substrate attachment in nerve growth cones and migrating cancer cells. The study of these mechanisms is essential for our understanding of diverse biological phenomena, in particular, neurite out-growth and pathfinding during brain development, and invasion of tissues by metastasizing cancer cells. The pseudopods of these two cellular systems share a number of properties.
Like nerve growth cones, cancer cell pseudopods also respond to certain repellents by activation of the PLA2 signal transduction cascade and collapse. Current experimentation is analyzing this pathway in further detail. Of particular interest are changes in the cascade that occur when cancer cells progress from a non-invasive to an invasive and metastatic phenotype. A further shared theme of growth cone and cancer cell studies is the functional role of cell surface glycoconjugates, such as cell adhesion and recognition molecules. Of particular interest is the fact that different growth cones express on their surfaces different sets of glycoconjugates. We have identified and characterized a highly variable glycoprotein (gp93) that is glycosylated differentially by different neuron types and is a novel candidate recognition molecule. gp93 is being cloned and sequenced and its functional role in cell-cell interactions investigated. The research in this laboratory combines a broad variety of approaches, ranging from behavioral assays of wild-type and mutant cells and various types of microscopy to methods of molecular biology a protein chemistry. Selected Publications
Mikule K, Gatlin JC, de la Houssaye BA, Pfenninger KH. Growth cone collapse induced by semaphorin 3A requires 12/15-lipoxygenase. J Neurosci. 2002 Jun 15;22(12):4932-41. Pfenninger KH, Laurino L, Peretti D, Wang XX, Rosso S, Morfini G, Cáceres A, Quiroga S (2003) Regulation of membrane expansion at the nerve growth cone. J Cell Sci. 116, 1209-1217. Wang XX, Dangott L, Pfenninger KH (2003) The Heterogeneous Growth Cone Glycoprotein gp93 is Identical to SIRP/SHPS-1/BIT. J Neurochem, 86, 55-60. Mikule K, Sunpaweravong S, Gatlin JC, Pfenninger KH (2003) Eicosanoid Activation of PKCe: Involvement in growth cone repellent signaling. J Biol Chem 278, 21168 – 77. Epub 2003 Mar 28. |
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The outgrowing neurite is tipped by an irregularly shaped, amoeboid enlargement, the nerve growth cone, which is the organelle controlling path-finding and synaptic recognition. It responds by turning, advancement or collapse to both positive (attachment) and negative (repellent) cues. The laboratory has identified and is analyzing a novel signal transduction pathway activated by growth cone repellents and causing pseudopod detachment from the growth substratum. The pathway involves, among other steps, the activation of cytosolic phospholipase A2 (PLA2) and protein kinase C and the phosphorylation of adhesion site proteins. Current research is designed to elucidate further the functional roles of different steps of the cascade, for example by misexpressing the relevant proteins in a neural cell line and studying growth cone behavior and biochemistry, with special emphasis on adhesion site structure and composition.