Steen Hansen

We are interested in two areas:

1. Ras and RAF are major oncogenes in human cancer. We are investigating the role of Rho-family GTP-binding proteins in oncogenic epithelial cell transformation by the Ras-activated RAF-MEK-ERK pathway. Altered Rho signaling is fundamental to acquisition of motile and proliferative capacities in cancer. Ras and RAF induce expression of Rnd3 and activation of Rac1, which both are members of the Rho-family. We established that Rnd proteins and Rac1 modulate signaling by p190 RhoGAP. In collaboration with Morten Frödin (BRIC), we moreover determined that Ras and RAF, through the effector kinase p90RSK, control expression of numerous genes that confer motile and invasive capacities through activation of Rac1. We are continuing efforts to further define Rac and Rho signaling pathways downstream of Ras and RAF.
2. The PAK-PIX-GIT complex is important in epithelial morphogenesis and oncogenic transformation. Class I PAKs are Cdc42/Rac effector molecules that bind directly to PIX proteins, which serve as activators of Cdc42/Rac. In turn, PIX proteins form stable complexes with GIT molecules, putative inactivators of the Arf family of GTP-binding proteins. We first demonstrated that PAK and PIX shuttle between focal adhesions and adherens junctions to regulate contact inhibition. Subsequently, we established that class I PAKs, PIX, and GIT proteins control pivotal processes in epithelial cells, including acquisition of invasive properties and protection from apoptosis. At the molecular level, one would expect that the PAK-PIX-GIT complex mediates cross talk between Arf- and Rho-family G proteins to regulate the activity of class I PAKs. Yet, despite our studies and those of others, defining the molecular mechanisms underlying the diverse properties of class I PAKs, PIX and GIT proteins remains a major ongoing challenge.