The Hippo signaling pathway has been identified as a central regulator of cell and organ size and tissue homeostasis modulating both proliferation and apoptosis. A number of previous studies revealed the pivotal role of hippo signaling and the tight control of its downstream effectors YAP and TAZ in maintaining podocyte integrity and preventing podocyte death. YAP and TAZ are transcriptional regulators that are controlled through a cascade of kinase activities that control YAP/TAZ nuclear localization and activation. Very recently, we could demonstrate that mechanosensory stimuli control YAP/TAZ activity in podocytes. Moreover, we found that both, knockout and transgenic expression of YAP in podocytes results in podocyte damage and proteinuria. In this project we aim to unravel the mechanisms how YAP/TAZ alterations contribute to podocyte integrity and how deregulation causes damage to podocytes. It is expected that this project, embedded in this consortium, will not only elucidate the molecular function of YAP/TAZ in FSGS but may suggest novel treatment options using modulation of YAP/TAZ associated signaling modules as a novel therapeutic principle in FSGS therapy.
Project related publications
Rinschen, M.M., F. Grahammer, A.K. Hoppe, P. Kohli, H. Hagmann, O. Kretz, S. Bertsch, M. Hohne, H. Gobel, M.P. Bartram, R.K. Gandhirajan, M. Kruger, P.T. Brinkkoetter, T.B. Huber, M. Kann, S.A. Wickstrom, T. Benzing, and B. Schermer. YAP-mediated mechanotransduction determines the podocyte's response to damage. Sci Signal 2017, 10(474).
Gandhirajan, R.K., M. Jain, B. Walla, M. Johnsen, M.P. Bartram, M. Huynh Anh, M.M. Rinschen, T. Benzing, and B. Schermer. Cysteine S-Glutathionylation Promotes Stability and Activation of the Hippo Downstream Effector Transcriptional Co-activator with PDZ-binding Motif (TAZ). J Biol Chem 2016, 291(22): 11596-607.
Bartram, M.P., S. Habbig, C. Pahmeyer, M. Hohne, L.T. Weber, H. Thiele, J. Altmuller, N. Kottoor, A. Wenzel, M. Krueger, B. Schermer, T. Benzing, M.M. Rinschen, and B.B. Beck. Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Hum Mol Genet 2016, 25(6): 1152-64.
Kann, M., S. Ettou, Y.L. Jung, M.O. Lenz, M.E. Taglienti, P.J. Park, B. Schermer, T. Benzing, and J.A. Kreidberg. Genome-Wide Analysis of Wilms' Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms. J Am Soc Nephrol 2015, 26(9): 2097-104.
Kohli, P., M.P. Bartram, S. Habbig, C. Pahmeyer, T. Lamkemeyer, T. Benzing, B. Schermer*, and M.M. Rinschen. Label-free quantitative proteomic analysis of the YAP/TAZ interactome. Am J Physiol Cell Physiol 2014, 306(9): C805-18. (* corresponding authorship)
Frank, V.#, S. Habbig#, M.P. Bartram, T. Eisenberger, H.E. Veenstra-Knol, C. Decker, R.A. Boorsma, H. Gobel, G. Nurnberg, A. Griessmann, M. Franke, L. Borgal, P. Kohli, L.A. Volker, J. Dotsch, P. Nurnberg, T. Benzing, H.J. Bolz, C. Johnson, E.H. Gerkes, B. Schermer*, and C. Bergmann*. Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression. Hum Mol Genet 2013, 22(11): 2177-85. (#shared first authorship; *shared corresponding authorship)
Habbig, S., M.P. Bartram, J.G. Sagmuller, A. Griessmann, M. Franke, R.U. Muller, R. Schwarz, M. Hoehne, C. Bergmann, C. Tessmer, H.C. Reinhardt, V. Burst, T. Benzing, and B. Schermer. The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ. Hum Mol Genet 2012, 21(26): 5528-38.
Habbig, S., M.P. Bartram, R.U. Muller, R. Schwarz, N. Andriopoulos, S. Chen, J.G. Sagmuller, M. Hoehne, V. Burst, M.C. Liebau, H.C. Reinhardt, T. Benzing, and B. Schermer. NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. J Cell Biol 2011, 193(4): 633-42.
Schermer, B. and T. Benzing. Lipid-protein interactions along the slit diaphragm of podocytes. J Am Soc Nephrol 2009, 20(3): 473-8.
