Education and Training

Ph.D. – Purdue University (Indianapolis, IN), 1998
Postdoctoral Training – Dartmouth College (Hanover, NH), 1998-2001
Research Scientist – Van Andel Institute (Grand Rapids, MI), 2001-2006

Summary

Our lab is interested in the basic mechanisms of cell motility and invasion, particularly as it relates to tumor growth and metastasis. Our efforts are concentrated on the study of podosomes, a specialized cell adhesion structure, enriched in matrix-remodeling proteases, and thereby capable of facilitating tissue invasion. Our study of a Src tyrosine kinase substrate and adaptor protein called Tks5 will be used to better define podosome formation and function and the role of podosomes in the development and progression of cancer.

Podosomes are invasive cytoskeletal structures made by invasive cell types including dendritic cells, macrophages, osteoclasts, vascular cells, various cancer cell lines, and Src-transformed fibroblasts (see figure). Podosomes are fine, actin-based protrusions of a cell’s ventral plasma membrane that penetrate the underlying extracellular matrix. Molecular studies suggest a similarity to focal adhesions including the presence of common markers like integrin receptors, tyrosine kinases, and actin-regulatory proteins. Distinguishing podosomes, however, is the enrichment of several classes of proteases with extracellular matrix remodeling activity. The other term for podosomes, invadopodia, derives from the invasive properties that these protease-rich structures confer upon cells.

Podosomes were originally described in cells transformed by an activated form of Src tyrosine kinase, an enzyme that has been closely linked with invasive forms of cancer. Src function is generally considered to be important for podosome formation and activity regardless of the cell type. It is localized to podosomes as are many tyrosine phosphorylated Src substrates. Among those is Tks5 (see figure). Tks5 has an amino terminal, lipid-binding PX domain that is both necessary and sufficient for podosome localization. It also contains numerous protein-binding modules within its five SH3 domains, multiple polyproline motifs, and potential phosphotyrosines. The 5th SH3 domain of Tks5 supports binding to ADAMs family metalloproteases. Tks5 can act as a controlling factor for podosome development in cancer cells, augmenting or attenuating their protease-driven invasive behavior depending on its degree of expression.

Research Goals

Our current efforts are directed towards the relative contributions of Src and Tks5 to podosome development among breast and prostate cancer cells and among normal cell types (macrophages, mural cells) of the tumor microenvironment. We consider their role in the assembly of scaffolds that permit podosome assembly, proteolysis of matrix proteins, cell invasion, and the progression of tumors.

Recent Publications

Abram C, DF Seals, I Pass, D Salinsky, L Maurer, TM Roth, and SA Courtneidge (2003) The adaptor protein Fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J Biol Chem 278, 16844-16851.

Seals DF and SA Courtneidge (2003) ADAMs family metalloproteases: multidomain proteins with multiple functions. Genes Dev 17, 7-30.

Seals DF, EF Azucena, I Pass, L Tesfay, R Gordon, M Woodrow, JH Resau, and SA Courtneidge (2005) The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7, 155-165.

Courtneidge SA, EF Azucena, I Pass, DF Seals, and L Tesfay (2005) The Src substrate Tks5, podosomes (invadopodia), and cancer cell invasion. Cold Spring Harbor Symposia on Quantitative Biology Symposium 70, 167-171.

Email:  dseals@wfubmc.edu