Vladimir Katanaev, Professeur invité (le groupe du Professeur Katanaev a déménagé à l'Université de Genève)
Vladimir Katanaev is born in Siberia and is a graduate of Krasnoyarsk State University and Pushchino branch of Moscow State University, Russia. He received his PhD in 2000 from the Institute of Biochemistry, University of Fribourg, working with Matthias Wymann on signal transduction in leukocyte chemotaxis. From 2000 to 2005 he worked as postdoctoral research fellow and subsequently as associate research scientist at the Department of Genetics and Development of Columbia University, New York, in the lab of Andrew Tomlinson. There he started his research on the Wnt/Frizzled signaling in Drosophila development. He continued to study this signaling cascade in Drosophila and mammalian cells as an independent group leader at the University of Konstanz, where he also completed his Habilitation in 2010. He joined the Department of Pharmacology and Toxicology in April 2011 as associate professor, relocating his laboratory from Konstanz to Lausanne.
Keywords: Wnt; Frizzled; signal transduction; G protein-coupled receptors; Drosophila; breast cancer
Animal development is a tightly regulated process, orchestrated by several types of intracellular signaling pathways, including signaling by the Wnt family of lipoglycoproteins and their G protein-coupled Frizzled receptors. The Wnt/Frizzled pathway is mostly silent in the adult. However, both improper overactivation and underactivation of this pathway can lead to diseases. Insufficient Wnt pathway activity underlies defects in tissue regeneration and the decreased proliferative potential of various stem cells; it may also lead to certain neurodegenerative disorders. On the other hand, misactivation of this signaling, e.g. through overproduction of the Wnt ligands or mutational activation of the downstream components of the pathway, promotes carcinogenesis, especially in the colon and breast.
We study signal transduction in this developmentally and medically important pathway using a combination of approaches, such as Drosophila genetics, mammalian cell culture, protein biochemistry, systems and cancer biology. We are particularly interested by the GPCR properties of Frizzled receptors, as well as identification and characterization of the signaling partners of the heterotrimeric Go protein - an immediate transducer of Frizzled receptors in flies and mammals. Having built a high-throughput in vitro assay monitoring Frizzled GPCR activation, we conduct multiple screening projects identifying novel antagonists of human Frizzleds as potential anti-cancer drugs. Our special attention is dedicated to the triple-negative breast cancer currently having no targeted therapies. Small molecules, antibodies, natural products, biologics, and repositioned approved drugs are among the anti-drug candidates currently being in the preclinical stages of development by our team.
Left: Image from the University of Lausanne highlights (www.unil.ch/getactu/wwwdpt/1394098424500/) the discovery of the double negative activity of Dhit on Gα-subunits (Gαo on the image) performed using a Pixar theme. Heterotrimeric G proteins can be activated by a GPCR (green button) but switched off through two different means: the GTPase-activating protein (GAP) activity of Dhit and the guanine nucleotide-exchange inhibitor (GDI) activity of Dhit. On the background of the image fragment of the structure of the Gao-Dhit complex is shown. (See Chen et al., Molecular Cell, 2014).
Right: Image from the University of Lausanne (www.unil.ch/getactu/wwwfbm/1408629988406/) highlights the discovery of another Gαo-interacting protein, neuronal Ankyrin, whose role in synapse formation and neurite outgrowth downstream from Gαo is conserved from Drosophila to mammals. On the image, mouse N2a cells are shown to form neurites upon Gαo activation in Ankyrin-dependent manner; the latter locates to the tips of the growing neurites (green). (See Lüchtenborg et al., Development, 2014).