Aberrant Rho GTPase activation and signaling in cancer development

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• Channing Der - University of North Carolina at Chapel Hill, NC
• Tuesday 14 October 2008, 13:00-14:00
• Lecture Theatre, Biochemistry, Department of (Sanger Building).

If you have a question about this talk, please contact Luca Pellegrini.

Like the Ras oncogene proteins, the Ras-related Rho family of small GTPases (20 human members) also function GDP /GTP-regulated binary switches in cell surface receptor-stimulated signal transduction pathways that regulate actin cytoskeletal organization, cell cycle progression, and gene expression. Thus it is not surprising that like Ras, considerable experimental analyses suggest that the aberrant activation of Rho GTPases can promote oncogenesis and cancer development. However, in contrast to Ras, mutationally activated Rho GTPases have not been found in human cancers. Instead, the emerging picture is that Rho GTPases are activated in cancers by a diversity of indirect mechanisms. For example, Rho GTPases function as GDP /GTP-regulated binary switches that cycle between active GTP -bound and inactive GDP -bound states. This cycle is controlled by both positive (guanine nucleotide exchange factors; RhoGEFs) and negative (GTPase activating proteins; RhoGAPs) regulatory proteins. Thus, it is the inappropriate activation of RhoGEFs (e.g., Tiam1, Asef, TEM4 ) or loss of function of RhoGAPs (e.g., DLC -1) that causes the indirect activation of Rho GTPases in human cancers. Other mechanisms include aberrant gene expression (Rnd3/RhoE, RhoGDI2, P-Rex-1 and Ect2) or gene splicing (Rac1b). Similar mechanisms also deregulate Rho GTPases in other human diseases (neurological and developmental disorders). The different biochemical and molecular mechanisms that cause aberrant Rho GTPase activation in human cancers will be presented.

This talk is part of the Research Seminars - Department of Biochemistry 2008/09 series.

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