Prof. E. Wolfgang Kühn
Our group studies ciliary signalling and cell polarity. Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited diseases in man (incidence 1:500-1:1000). The kidneys of affected individuals progressively enlarge with multiple fluid filled cysts and over half of the patients require dialysis or kidney transplantation before the age of 60. Mutations in 2 genes are responsible: Pkd1 (85% of cases), a large orphan receptor involved in multiple signal transduction pathways and Pkd2 (15% of cases), a non-selective cation channel of the transient receptor potential family (TRPP2). Both proteins interact and are linked to the primary cilium, a filiform microtubular organelle and signalling platform. In the past decade mutations in ciliary proteins have been linked to a pleiotropic disease spectrum named ‘the ciliopthies’ which next to PKD encompass disorders of the eye, the skeleton, the olfactory system, situs, bronchi, brain, reproductive system and metabolism. To gain insight into the pathogenesis of cyst formation our aim is to characterize the role of polycystin 1, TRPP2 and cilia in the maintenance of tubular epithelial cell homeostasis and to study how disruption of these determinants leads to disturbed polarity and proliferation. For this purpose we study epithelial cells in flow chamber set-ups and use life cell imaging approaches for dynamic analysis of the cytoskeleton and cellular polarity. These tools are complemented by inducible gain of function and loss of function systems to gain insight into how the disruption of ciliary proteins can explain cyst formation and to identify possible drug targets for the treatment of ADPKD.
10 selected publications
- Crystal structures of IFT70/52 and IFT52/46 provide insight into intraflagellar transport B core complex assembly.
Taschner M, Kotsis F, Braeuer P, Kuehn EW, Lorentzen E (2014).
J Cell Biol 207, 269-282
- Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells.
Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Klasener K, Ruf S, Sonntag AG, Maerz L, Grellscheid SN, Kremmer E, Nitschke R, Kuehn EW, Jonker JW, Groen AK, Reth M, Hall MN, Baumeister R (2013).
Cell 154, 859-874
- ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.
Hoff S, Halbritter J, Epting D, Frank V, Nguyen TM, van Reeuwijk J, Boehlke C, Schell C, Yasunaga T, Helmstadter M, Mergen M, Filhol E, Boldt K, Horn N, Ueffing M, Otto EA, Eisenberger T, Elting MW, van Wijk JA, Bockenhauer D, Sebire NJ, Rittig S, Vyberg M, Ring T, Pohl M, Pape L, Neuhaus TJ, Elshakhs NA, Koon SJ, Harris PC, Grahammer F, Huber TB, Kuehn EW, Kramer-Zucker A, Bolz HJ, Roepman R, Saunier S, Walz G, Hildebrandt F, Bergmann C, Lienkamp SS (2013).
Nat Genetics 45, 951-956 (2013).
- Kif3a Guides Microtubular Dynamics, Migration and Lumen Formation of MDCK Cells.
Boehlke C, Kotsis F, Buchholz B, Powelske C, Eckardt KU, Walz G, Nitschke R, Kuehn EW (2013).
PloS one 8, e62165
- Primary cilia regulate mTORC1 activity and cell size through Lkb1.
Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, Beyer T, Janusch H, Hamann C, Godel M, Muller K, Herbst M, Hornung M, Doerken M, Kottgen M, Nitschke R, Igarashi P, Walz G, Kuehn EW (2010).
Nat Cell Biol 12: 1115-1122.
- Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels.
Boehlke C, Bashkurov M, Buescher A, Krick T, John AK, Nitschke R, Walz G, Kuehn EW (2010).
J Cell Sci 123: 1460-1467.
- TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum.
Wegierski T, Steffl D, Kopp C, Tauber R, Buchholz B, Nitschke R, Kuehn EW, Walz G, Kottgen M (2009).
EMBO J 28: 490-499
- TRPP2 and TRPV4 form a polymodal sensory channel complex.
Kottgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer-Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G § (2008).
J Cell Biol 182: 437-447.
- Flow modulates centriole movements in tubular epithelial cells.
Kotsis F, Nitschke R, Doerken M, Walz G, Kuehn EW (2008).
Pflugers Archiv 456: 1025-1035.
- Kidney injury molecule-1 expression in murine polycystic kidney disease.
Kuehn EW, Park KM, Somlo S, and Bonventre JV (2002).
American journal of physiology Renal physiology 283, F1326-1336