Cytoskeletal Signaling

Grosse Lab

Dr. Robert Grosse, Professor and Chair of Pharmacology, Medical Faculty  - phone: +49 (0)6421-28-65001  email: robert.grosse@staff.uni-marburg.de

CONTACT: Institute of Pharmacology, Faculty of Medicine, University of Marburg, Karl-von-Frisch-Str. 1, 35043 Marburg, Germany

Administrative Assistant: Tanja Pfeffer-Eckel – phone: +49(0)6421-28-65000  email: pfeffer@staff.uni-marburg.de

We aim at understanding some of the principal cytoskeletal mechanisms that control cell shape and motility. Our goal is to identify and characterize relevant cytoskeletal signaling components that may represent novel molecular targets in particular for cancer and anti-invasive therapies. One focus of our lab is to study signal regulations of actin dynamics through the formin family of actin nucleators and their interplay with transcriptional events, which impinges on cancer cell behavior and invasiveness.

Our research is generously funded by the: 

DFG / Deutsche Krebshilfe / HFSP / Wilhelm Sander-Stiftung

logos

Research
Dynamic rearrangement of the cytoskeleton regulates responses to a variety of extracellular signals that allow cells to move or to change shape. Actin dynamics is controlled by defined signaling pathways, which orchestrate the activity of distinct actin nucleation factors. The largest family of actin nucleators is represented by the formins, which are characterized by their highly conserved formin homology (FH) domain. Many diaphanous formins are regulated through physical interactions with Rho family proteins, which can function as molecular switches to relay signal instructions to various cellular responses. Interestingly, some formins such as mDia1 and mDia2 govern transcriptional activity of the Serum Response Factor (SRF) through their effects on actin polymerization. One current major focus of our lab is to understand formin-induced nuclear actin assembly for nuclear dynamics, which may have implications for cancer cell behavior, differentiation and nuclear architecture. For our investigations we employ or develop methods for 3D-collagen live cell assays, spatiotemporal optogenetic regulation of endogenous diaphanous or mDia formins as well as microscopy-based cytoskeletal analysis in living cells.

Epithelial lumen formation assay

lumen2

Organotypic epithelial lumen formation. Human breast epithelial cells were (MCF10A) grown in 3D matrices to study junctional actin dynamics. Actin in green, nuclei in blue. 

for more information please see: Grikscheit et al., J. Cell Biol. 209, (2015)

Optogenetic release of endogenous formin autoinhibition with LOV-DAD

Cartoon of a module illustrating light-induced activation of endogenous mDia. Per-ARNT-Sim (PAS) domain and a c-terminal Jα-helix as LOV2 domain fused to the Diaphanous Autoregulatory Domain (DAD). Illumination with blue light leads to release of endogenous mDia autoinhibition.

for more information please see: Baarlink et al., Science 340, (2013); DOI: 10.1126/science.1235038

 

Nuclear Actin Network

Serum (or LPA) can trigger rapid formation of nuclear actin network assembly within seconds.

for review please see: Baarlink & Grosse, Nucleus, (2014); Plessner & Grosse, Eur J Cell Biol (2015)

 

Team

 

 

 

Alumni

  • Dr. Pilar Chinchilla
  • Dr. Xenia Goulimari, PharmAthene
  • Dr. Jameel Khan, Lifecode Technologies Ltd.
  • Dr. Thomas Kitzing, Boehringer Ingelheim
  • Dr. Eva-Maria Kleinschnitz
  • Dr. Helga Knieling, Caritas Hospital, Saarbrucken
  • Dr. Camilla Kreßner
  • Dr. Alexander Nuernberg, Roche, Basel
  • Dr. Gaurav Pathria, Sanford-Burnham-Prebys, LaJolla, California
  • Dr. Vladimir Purvanov, Institute Biochtechnology Thurgau, University of Konstanz,
  • Dr. Eva Schwaibold, University of Göttingen
  • Dr. Haicui Wang, University of Cologne
Selected Publications
  • Wang Y, Arjonen A, Pouwels J, Ta H, Pausch P, Bange G, Engel U, Pan X, Fackler OT, Ivaska J, Grosse R (2015) Formin-like 2 Promotes ß1-integrin Trafficking and Invasive Motility Downstream of PKCalpha Dev Cell 34:475-483.    Faculty of 1000 
  • K. Grikscheit, T. Frank, Y. Wang, and R. Grosse (2015) Junctional actin assembly is mediated by Formin-like 2 downstream of Rac1
    J. Cell Biol. 209:367-376.   JCB Journal Club – Biosights
  • Plessner M, Melak M, Chinchilla P, Baarlink C, Grosse R. (2015) Nuclear F-actin Formation and Reorganization upon Cell Spreading. J .Biol. Chem. 290:11209-16.  JBC Papers of the Week, JBC podcast
  • Purvanov V., Holst M., Khan J., Baarlink C., Grosse R. (2014) G-protein-coupled receptor signaling and polarized actin dynamics drive cell-in-cell invasion eLife. 3:e02786.
  • Grosse R. and Vartiainen M. (2013) To be or not to be assembled: progressing into nuclear actin filaments. Nat. Rev. Mol. Cell Biol. 14: 693-697.
  • Baarlink C., Wang H. and Grosse R. (2013) Nuclear Actin Network Assembly by Formins Regulates the SRF Coactivator MAL. Science 340:864-867.   Editors Choice Science Signaling; Research Highlight in Nat Rev Mol Cell Biol.
  • Nürnberg A., Kitzing T., and Grosse R. (2011) Nucleating actin for invasion. Nat. Rev. Cancer 11:177-187.
  • Baarlink, Brandt, and Grosse (2010) SnapShot: Formins Cell 142.
  • Brandt D.T., Baarlink C., Kitzing T.M., Kremmer E., Ivaska J., Nollau, P., Grosse R. (2009) SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin. Nat. Cell Biol. 11:557-568.    Faculty of 1000
  • Kitzing T.M., Sahadevan A.S., Brandt D.T., Knieling H., Hannemann S., Fackler O.T., Großhans J., Grosse R. (2007) Positive feedback between Dia1, LARG and RhoA regulates cell morphology and invasion. Genes Dev. 21:1478-1483.    Faculty of 1000
  • Brandt D.T., Marion S., Griffiths G., Watanabe T., Kaibuchi K., Grosse R. (2007) Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J. Cell Biol. 178:193-200.    Faculty of 1000
  • Faix J, Grosse R (2006) Staying in shape with forming Dev. Cell 10:693-706.
  • Goulimari P, Kitzing TM, Knieling H, Brandt DT, Offermanns S, Grosse R (2005) Galpha12/13 is essential for directed cell migration and localised Rho-Dia1 function J. Biol. Chem 280:42242-51.