Steen Hansen

The Ras superfamily consists of more than 100 members divided into five families: Ras, Rho, Arf, Rab, and Ran. Ras-like G proteins typically function as molecular switches by cycling between an active, GTP-bound and an inactive, GDP-bound state. Ras-like G proteins rely on GTPase-activating proteins (GAPs) to promote GTP hydrolysis and guanine nucleotide exchange factors (GEFs) to facilitate the exchange of GDP for GTP. The GEFs and GAPs exert spatial and temporal control of Ras-like G protein signaling. They also serve as effector proteins, permitting cross-talk between various Ras-like G proteins. My current work focuses on a subset of Rho GEFs and GAPs and the roles that these molecules play in epithelial morphogenesis and oncogenic transformation.

First, I am interested in DOCK protein signaling. DOCK proteins are GEFs for Rac and CDC42 proteins of the Rho branch of Ras-like proteins. My lab previously demonstrated that GIT proteins, which possess GAP activity toward Arf proteins, repress Crk- and Rac-regulated motile and invasive capacities. We subsequently established that GIT proteins exert these functions by negatively regulating the activity of the RacGEF DOCK5. In ongoing work, we have determined a role for DOCK5 downstream of Ras and are actively pursuing the significance of this discovery to human cancer cells with oncogenic Ras mutations.

Second, I am interested in the p190 RhoGAPs p190A and p190B. In past work, we have established that p190A and p190B mediate pivotal cross-talk between various Rho proteins. ARHGAP35, the gene that encodes p190A, is a major cancer gene. Recently, we defined a mechanism whereby p190A acts as a tumor suppressor: p190A and its ortholog p190B repress YAP-TEAD-mediated gene transcription to promote contact inhibition of cell proliferation. Currently, we are seeking to refine our understanding of the link between p190 RhoGAP and Hippo signaling, insight that should prove useful in improving therapy for cancers with loss of p190A expression.