Scientific Report 2005

Immunology

Promotion of Cell Migration and Invasion by Tyrosine Kinase Signaling

D.D. Schlaepfer, J.A. Bernard-Trifilo, X.L. Chen, A. Chi, D.A. Hanson, S. Hou, S.T. Lim, Y.M. Lim, S.K. Mitra, J. Molina, S. Uryu

We wish to understand how intracellular signaling networks coordinate a complex biological response such as cell motility. In order for a cell to correctly process different environmental stimuli, these networks must contain critical intracellular signaling proteins that act as signal “integrators.” These proteins should be activated by various extracellular inputs and act to regulate multiple downstream signaling pathways. One such integrator is focal adhesion kinase (FAK), an intracellular protein tyrosine kinase that is associated with sites of binding of integrin receptors to matrix proteins such as fibronectin. FAK catalytic activity is enhanced by integrin binding to fibronectin, and FAK tyrosine phosphorylation is increased in a receptor-proximal fashion by transmembrane growth factor and G protein–linked receptors.

In many cells, increased FAK phosphorylation promotes binding of the protein tyrosine kinase c-Src to FAK, thereby generating a dual FAK-Src protein tyrosine kinase signaling complex. Because genetic inactivation of FAK or Src results in the inhibition of cell migration, our research strategy is to perform rescue and/or gain-of-function assays in cells that lack FAK expression. We are elucidating the importance of FAK catalytic activity, FAK-Src signaling connections, novel interactions between FAK and its binding partners, and the molecular basis for FAK relocalization to distinct intracellular sites after treatment with motility-promoting stimuli. Additionally, we are investigating the effects of the upregulated expression of the FAK-related proline-rich tyrosine kinase 2 in cells that lack FAK.During cancer progression, tumor cells can become highly motile and invasive. These properties contribute to tumor spread and metastasis. Elevated FAK expression has been correlated with increased tumor growth and metastasis. However, the molecular signaling connections that link FAK to tumorigenesis remained undefined. The possibility that FAK-mediated signaling may promote increased tumor growth has generated much interest in determining the molecular mechanisms of FAK function in both normal cells and tumor cells.

We found that FAK-Src signaling promotes an invasive cell phenotype in a manner that is distinct from the signaling role of FAK in promoting cell motility. In these studies, we are using live-cell imaging, recombinant viral vectors, RNA interference, cell culture–based signaling, and in vivo tumor growth and experimental metastasis assays to elucidate the molecular signaling connections of FAK in tumorigenesis.

Publications

Mitra, S.K., Hanson, D.H., Schlaepfer, D.D. Focal adhesion kinase: in command and control of cell motility. Nat. Rev. Mol. Cell. Biol. 6:56, 2005.