Receptor biology and signaling
Our research aims to increase the understanding of basic pharmacology and underlying mechanisms of signal transduction and signaling specificity mediated by the Class Frizzled (FZD) receptors.
In mammals 10 FZDs (FZD1-10) are known. The FZDs are - among other ligands - activated by 19 mammalian WNTs, a group of secreted lipoglycoproteins with an important role in embryonic development, stem cell regulation and human diseases, such as cancer. So far, it remains obscure, which WNTs activate which FZDs and how ligand binding specifies the downstream signaling events.
Our goal is to map WNT-FZD interaction profiles and to characterize basic pharmacological parameters of distinct WNT/FZD pairs. The ultimate goal, of course, is to find mechanisms that could be employed at therepeutic targets to improve current therapy in human disease as diverse as cancer, neurodegenerative diseases, bone disease, etc.
Using biochemical and anatomical as well as live-cell imaging techniques the dynamics of receptor localisation and association of intracellular signalling molecules are investigated in recombinant cell systems and glial cellular models as well as in vivo.
Javier Becerril Ortega
|PhD, postdoctoral fellow|
|Jenny Dahlström||Med kand, master's student|
|Tilman Polonio||Student from Heidelberg University/ Germany|
|Roger Helbig||Phd, postdoctoral fellow|
|Tobias Ludwig||Student from the Free University of Berlin, Germany|
Natália Assaife Lopes
|PhD student, Faculty of Medicine, University of Lisbon, Portugal|
|Master's student from the Free University of Berlin, Germany|
|Frank Brand||Master's student from the Lausitz University of Applied Sciences, Germany|
The image shows the subcellular distribution of dishevelled (DVL2-myc; red) in transiently transfected Hek293 cells. DVL2-myc is either distributed evenly throughout the cytoplasm, or aggregates in a punctate pattern of variable size (see also Bryja et al, J Cell Sci 2007).
The general aim of the project is to generate pharmacological information about the Wnt/Frizzled signaling system as well as to clarify some major questions regarding Frizzled-mediated cellular communication. Issues such as WNT-FZD interaction and selectivity, signaling trafficking, FZD coupling to the phosphoprotein Disheveled as well as heterotrimeric G proteins are the focus of our work. To investigate those questions we use protein biochemistry, determination of second messengers, Calcium imaging, confocal microscopy and live cell imaging.
Graphical abstract from Halleskog et al 2013 (Cellular Signalling)
In addition to the pharmacological assessment of FZD function, we try to understand the role of WNT/FZD signaling in the macrophages of the brain, the microglia. Our recent publication (PhD project of Carina Halleskog) shed light on the proinflammatory effects of WNTs on microglia. These cells have also provided exciting insight into the role of heterotrimeric G proteins in WNT signaling in a physiologically relevant cellular environment with natural receptor stoichiometry.
Research support - past and present
Vetenskapsrådet, Hjärnfonden, Cancerfonden, Karolinska Institutet, Knut & Alice Wallenberg Stiftelse, Signhild Engkvists Stiftelse, Tore Nilson Stiftelse, Signe & Olof Wallenius Stiftelse, Max & Edith Follins Stiftelse, Fernströms Stiftelsen, Alex & Eva Wallström Stiftelse, Jeanssons Stiftelse, Åke Wiberg Stiftelse, Åhlén Stiftelse, Stiftelsen Olle Engkvist Byggmästare, Socialstyrelsen, STINT, KI/NIH Joint PhD, KID, GACR (Czech Science Foundation), FP7 Marie Skłodowska-Curie actions
Master's and PhD projects
Please see Master's and PhD projects from the lab.
Recruiting a postdoctoral fellow (financed by fellowship for 2 years)
Last application date: 22nd of August 2016
The applicant must be ambitious and demonstrate a strong interest in GPCR pharmacology and protein biochemistry. An appropriate background to develop the proposed research area would be biochemistry, GPCR pharmacology and molecular biology. Positive attitude, high motivation and an intrinsic drive to push the borders of our current knowledge are a prerequisite for recruitment. The project is in collaboration with Thomas Sakmar at Rockefeller University.
Interested applicants should contact group leader Gunnar Schulte directly with inquiries.
I would be happy to assist with applications for external support in form of postdoctoral or PhD student fellowships (see list pdf ). I strongly encourage fellows eligible for postdoctoral application to Hjärnfonden and SSMF to contact me with a letter of interest, CV and letters of recommendation.
Please see Gallery - Gunnar Schulte group
High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes.
Exp. Cell Res. 2015 Dec;339(2):280-8
Systematic mapping of WNT-FZD protein interactions reveals functional selectivity by distinct WNT-FZD pairs.
J. Biol. Chem. 2015 Mar;290(11):6789-98
Assessment of Frizzled 6 membrane mobility by FRAP supports G protein coupling and reveals WNT-Frizzled selectivity.
Cell. Signal. 2014 Sep;26(9):1943-9
Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6.
FASEB J. 2014 May;28(5):2293-305
WNT-3A and WNT-5A counteract lipopolysaccharide-induced pro-inflammatory changes in mouse primary microglia.
J. Neurochem. 2013 Jun;125(6):803-8
Heterotrimeric G protein-dependent WNT-5A signaling to ERK1/2 mediates distinct aspects of microglia proinflammatory transformation.
J Neuroinflammation 2012 May;9():111
Recombinant WNTs differentially activate β-catenin-dependent and -independent signalling in mouse microglia-like cells.
Acta Physiol (Oxf) 2011 Nov;203(3):363-72
WNT-5A stimulates the GDP/GTP exchange at pertussis toxin-sensitive heterotrimeric G proteins.
Cell. Signal. 2011 Mar;23(3):550-4
WNT signaling in activated microglia is proinflammatory.
Glia 2011 Jan;59(1):119-31
Beta-arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways.
EMBO Rep. 2008 Dec;9(12):1244-50
Inhibition of endocytosis blocks Wnt signalling to beta-catenin by promoting dishevelled degradation.
Acta Physiol (Oxf) 2007 May;190(1):55-61
Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo.
Proc. Natl. Acad. Sci. U.S.A. 2007 Apr;104(16):6690-5
Frizzleds and WNT/β-catenin signaling--The black box of ligand-receptor selectivity, complex stoichiometry and activation kinetics.
Eur. J. Pharmacol. 2015 Sep;763(Pt B):191-5
WNT/Frizzled signalling: receptor-ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3.
Br. J. Pharmacol. 2014 Mar;171(5):1195-209
International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors.
Pharmacol. Rev. 2010 Dec;62(4):632-67
beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways?
Br. J. Pharmacol. 2010 Mar;159(5):1051-8
The Frizzled family of unconventional G-protein-coupled receptors.
Trends Pharmacol. Sci. 2007 Oct;28(10):518-25