Jun-Lin Guan,College of Veterinary Medicine

The Guan laboratory is studying the signal transduction mechanisms involved in cell-matrix and cell-cell interactions. One line of research centers on examining signal transduction by the integrin family of cell adhesion receptors in cell proliferation and migration. Using a variety of biochemical and molecular biological approaches, the laboratory is involved in identifying intracellular molecules that participate in integrin signaling, characterizing these molecular interactions in vitro, as well as testing the importance of these molecules and interactions at the cellular level by using transfection approaches and also in appropriate animal models.

Of particular emphasis has been the role of the focal adhesion kinases (FAK) and its interacting proteins in integrin signaling. The Guan laboratory has shown that FAK interacts with other key signaling molecules such as Src and PI-3 kinase as well as the cytoskeletal protein talin. Using a CHO cell transfection system, they found that FAK and its interactions with Src are critical in signal transduction of integrins leading to cell migration on matrix proteins.

In related studies, the Guan group showed that FAK interactions with PI-3 kinase and a novel phosphoprotein (pp200) are regulated by PDGF. This as well as other evidence suggest that FAK may be a point of convergence of several signal transduction pathways. Current efforts are directed at examining the potential role of FAK in PDGF-induced cytoskeleton reorganization and cell migration.

The laboratory has also recently isolated the cDNA clone encoding a protein tyrosine kinase homologous with FAK. This new tyrosine kinase (Pyk2, or CAKb) is localized in cell-cell junctions, suggesting a potential role in cell-cell adhesions. Recent studies have indicated that the cadherin family of cell adhesion molecules can also transduce signals across the plasma membrane to regulate cell proliferation and differentiation. These studies also hinted at a role for protein tyrosine kinases in these processes. Using available reagents for the new kinase, its role in mediating signaling by cadherins will be investigated.

The Guan group also will examine whether the new kinase interacts with other cellular proteins involved in signaling, and if so, the binding sites will be mapped in order to ultimately establish the role of these interactions. Finally, efforts are underway to generate sufficient amounts of FAK and the limit FAK-binding regions from its cellular binding partners to perform a structural examination of how these interactions occur. The long-term goal will be to compare the molecular details of these interactions with those that emerge from structural studies of Pyk2 complexes.