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Regulation of Cell Invasion by the Podosome/Invadopod Protein Tks5

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abstract
Tks5 is a Src tyrosine kinase substrate and scaffolding protein for specialized cytoskeletal structures called podosomes/invadopodia. My doctoral thesis has focused on how Tks5 regulates the formation of these related structures and their impact on the invasive phenotype of cells. The podosomes of macrophages enable tissue invasion during immunosurveillance and wound healing. Using model THP1 macrophages, my studies have shown that Tks5 can directly control podosome-associated matrix degradation and invasion through collective changes in adhesion, chemotaxis, and the expression/proteolytic activity of MMP9. I have further shown that Src family kinase-dependent Tks5 phosphorylation is necessary for podosome formation and matrix degradation activity in macrophages. A similar investigation was carried out on the invadopodia of prostate cancer cell lines. It is thought that invadopodia may drive tumor progression in this model. This is supported by my studies showing that overexpression of Tks5 alone is sufficient to induce invadopodia formation and degradation activity in poorly invasive LNCaP cells, and similar to what we have shown in macrophages, this increase in degradation activity is correlated with Src-dependent Tks5 phosphorylation. Taken together, these studies illustrate the importance of Src/Tks5 signaling in the invasive properties of these cell types.
subject
biomarker
cytoskeleton
Invadopodia
invasion
metastasis
Podosome
contributor
Burger, Karen Lynn (author)
Seals, Darren F (committee chair)
Alexander-Miller, Martha (committee member)
Kridel, Steven J (committee member)
Miller, Mark S (committee member)
Metheny-Barlow, Linda J (committee member)
date
2013-06-06T21:19:22Z (accessioned)
2013 (issued)
degree
Cancer Biology (discipline)
10000-01-01 (liftdate)
embargo
forever (terms)
identifier
http://hdl.handle.net/10339/38515 (uri)
language
en (iso)
publisher
Wake Forest University
title
Regulation of Cell Invasion by the Podosome/Invadopod Protein Tks5
type
Dissertation

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