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Receptor biology and signaling – Schulte Lab
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.
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About us
Illustration from Kowalski-Jahn & Schihada et al. 2021
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A NanoBiT/BRET assay design allowed Pawel Kozielewicz to assess WNT binding to a full length FZD for the first time. This breakthrough allowed pharmacological characterization of WNT-FZD binding (Kozielewicz et al. 2021; Wesslowski & Kozielewicz et al. 2020).
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The class F of G protein-coupled receptors (GPCRs) consists of ten Frizzleds (FZD1-10) and Smoothened (SMO). 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. In the Schulte lab, we investigate how ligands activate FZDs in order to initiate intracellular changes. In this effort, we focus on ligand-receptor interaction, ligand-induced conformational changes in the receptor and aspects of conformational selection determining which downstream signaling pathways are activated. Thereby we hope to provide better insight into WNT-FZD binding mechanisms and selectivity and how intracellular signaling is initiated and specified by the individual FZD paralogues.
Fluorescent sensors based on cpGFP enabled Hannes Schihada in the Schulte lab to visualize WNT-induced conformational changes in several FZD paralogues (Schihada et al. 2021).
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During the recent years, we have developed expertise in the use and design of genetically encoded biosensors that monitor ligand binding to FZDs, FZD conformational dynamics, FZD-effector binding and downstream effector activation. Furthermore, we combine these live cell assessments of the most upstream events of WNT-induced effects with in silico approaches such as molecular dynamics simulations and computational modelling to provide mechanistic insight into receptor activation and receptor complex dynamics on a molecular level.
One of the most important concepts that we have developed and that presents an important contribution to the field is the idea that FZDs are - similar to other GPCR – molecular machines that are defined by a structural flexibility and dynamics. Appreciation of this intrinsic flexibility is the basis for understanding receptor activation, receptor-mediated signal initiation and for targeting FZDs for therapy. Several important contributions from the Schulte lab have contributed to understand this central phenomenon (Wright and Kozielewicz et al. 2019; Kozielewicz et al. 2020; Turku et al. 2021; Kowalski-Jahn and Schihada et al. 2021; Schihada et al. 2021).
Our goal is to understand the complexity of WNT-induced events that determine the kinetics and nature of WNT signaling pathways governing embryonic development and tissue homeostasis. Since deregulated WNT signaling results in devastating diseases exemplified by many different and common forms of tumors (e g breast, intestinal, pancreatic cancer), bone disease, fibrosis and neurological disorders, we are convinced that targeting FZDs pharmacologically will open exciting strategies for the therapy of severe diseases.
Understanding how FZDs mediate WNT signaling to drive proliferation in a tumor or in a fibrotic tissue will allow us to design drugs that interfere with this message for therapeutic use. Our lab has shown for the first time that FZDs can be pharmacologically targeted by small molecule drugs (Kozielewicz et al. 2020) and we are currently developing this strategy to find drug-like compounds for anti-cancer treatment.
The computer simulation shows the interaction between FZD6 (white) and the small drug-like molecule SAG13 (purple).
The recent advances in our understanding of the details of FZD activation have been possible because of the development of biophysical assays that are suitable to dissect mechanistic aspects of signaling in an unprecedented manner. Furthermore, these assays are building the technological basis for drug screening efforts, which will explore the chemical matter on the quest for new drugs to treat cancer and other devastating human disorders.
Wright SC, Kozielewicz P, Kowalski-Jahn M, Petersen J, Bowin CF, Slodkowicz G, Marti-Solano M, Rodríguez D, Hot B, Okashah N, Strakova K, Valnohova J, Babu MM, Lambert NA, Carlsson J, Schulte G. A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. Nat Commun. 2019 Feb 8;10(1):667. doi: 10.1038/s41467-019-08630-2. PMID: 30737406
Kozielewicz P, Turku A, Bowin CF, Petersen J, Valnohova J, Cañizal MCA, Ono Y, Inoue A, Hoffmann C, Schulte G. Structural insight into small molecule action on Frizzleds. Nat Commun. 2020 Jan 21;11(1):414. doi: 10.1038/s41467-019-14149-3. PMID: 31964872
Wesslowski J, Kozielewicz P, Wang X, Cui H, Schihada H, Kranz D, Karuna M P, Levkin P, Gross JC, Boutros M, Schulte G, Davidson G. eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length Frizzled. J Biol Chem. 2020 Jun 26;295(26):8759-8774. doi: 10.1074/jbc.RA120.012892. Epub 2020 May 7. PMID: 32381507
Schihada H, Kowalski-Jahn M, Turku A, Schulte G. Deconvolution of WNT-induced Frizzled conformational dynamics with fluorescent biosensors. Biosens Bioelectron. 2021 Apr 1;177:112948. doi: 10.1016/j.bios.2020.112948. Epub 2020 Dec 30. PMID: 33486136
Kozielewicz P, Shekhani R, Moser S, Bowin CF, Wesslowski J, Davidson G, Schulte G. Quantitative Profiling of WNT-3A Binding to All Human Frizzled Paralogues in HEK293 Cells by NanoBiT/BRET Assessments. ACS Pharmacol Transl Sci. 2021 May 11;4(3):1235-1245. doi: 10.1021/acsptsci.1c00084. eCollection 2021 Jun 11. PMID: 34151213
Turku A, Schihada H, Kozielewicz P, Bowin CF, Schulte G. Residue 6.43 defines receptor function in class F GPCRs. Nat Commun. 2021 Jun 24;12(1):3919. doi: 10.1038/s41467-021-24004-z. PMID: 34168128
Xu L, Chen B, Schihada H, Wright SC, Turku A, Wu Y, Han GW, Kowalski-Jahn M, Kozielewicz P, Bowin CF, Zhang X, Li C, Bouvier M, Schulte G, Xu F. Cryo-EM structure of constitutively active human Frizzled 7 in complex with heterotrimeric Gs. Cell Res. 2021 Jul 8. doi: 10.1038/s41422-021-00525-6. Online ahead of print. PMID: 34239071
Kowalski-Jahn M, Schihada H, Turku A, Huber T, Sakmar TP, Schulte G. Frizzled BRET sensors based on bioorthogonal labeling of unnatural amino acids reveal WNT-induced dynamics of the cysteine-rich domain. Sci Adv. 2021 Nov 12;7(46):eabj7917. doi: 10.1126/sciadv.abj7917. Epub 2021 Nov 10. PMID: 34757789
Funding
- Alex & Eva Wallström Stiftelse
- Cancerfonden
- Emil och Wera Cornells Stiftelse
- EUbOPEN
- Fernströms Stiftelsen
- FP7 Marie Skłodowska-Curie actions
- GACR (Czech Science Foundation)
- Hjärnfonden
- Jeanssons Stiftelse
- Karolinska Institutet
- KI/NIH Joint PhD
- KID
- Knut & Alice Wallenberg Stiftelse
- Max & Edith Follins Stiftelse
- Novonordiskfonden
- Signe & Olof Wallenius Stiftelse
- Signhild Engkvists Stiftelse
- Socialstyrelsen
- Stiftelsen Olle Engkvist Byggmästare
- STINT
- Tore Nilson Stiftelse
- Vetenskapsrådet
- Wenner-Gren Foundation
- Åhlén Stiftelse
- Åke Wiberg Stiftelse
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Staff and contact
Group leader
- Gunnar SchulteProfessor | Docent
All members of the group
- Louise AnderssonAffiliated to Research
- Julien BousPostdoctoral Researcher
- Björn ForsbergAffiliated to Research
- Lukas GraetzAffiliated to Research
- Julia KinsolvingPhd Student
- Paweł KozielewiczAssistant Professor | Team Leader
- Gaia MartinianiAffiliated to Research
- Magdalena ScharfPostdoctoral Researcher
- Gunnar SchulteProfessor | Docent
- Rawan ShekhaniPhd Student
- Jan VossAffiliated to Research
Alumni
- Maria Kowalski-Jahn, postdoc
- Ainoleena Turku, postdoc
- Shane Wright, postdoc
- Elisa Arthofer, PhD
- Fredrik Brand, Master's student from the Lausitz University of Applied Sciences, Germany
- Jenny Dahlström, Med kand, master's student
- Jacomijn Dijksterhuis, PhD
- Carina Halleskog, PhD
- Rober Helbig, PhD, postdoctoral fellow
- Belma Hot, PhD
- Michaela Kilander, PhD
- Natália Assaife Lopes, PhD student, Faculty of Medicine, University of Lisbon, Portugal
- Tobias Ludwig, Student from the Free University of Berlin, Germany
- Javier Becerril Ortega, PhD, postdoctoral fellow
- Julian Petersen, PhD
- Tilman Polonio, Student from Heidelberg University, Germany
- Jana Valnohova, PhD
- Alice Weithäuser, Master's student from the Free University of Berlin, Germany
- Carl Fredrik Bowin (PhD student)
- Hannes Schihada, postdoc
Team - Molecular pharmacology of GPCRs
Molecular Pharmacology of G protein-coupled receptors
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We are interested in understanding the role of GPCRs in health and disease, with a focus on cancer and obesity. Of particular interest to us are understudied orphan GPCRs. These receptors bear untapped therapeutic potential and a lof of them are highly expressed or mutated in these diseases. To shed light on the functions of orphan GPCRs in these conditions, we aim to employ an integrative approach. We will study these proteins in different systems, ranging from HEK293 cells to patients' samples, and investigate phenomena at different levels: from receptor conformational changes to impact on cell phenotype.
Our methodologies include but are not limited to:
- Bioluminescence resonance energy transfer (BRET)
- CRISPR-Cas9 genome editing
- Molecular modelling with ligand docking and molecular dynamics simulations
- Proximal labelling techniques
- Analysis of large genomic datasets
Projects:
- Analysis of the role of orphan GPCRs in cancer
- Investigations into orphan GPCRs as regulators of metabolism
- Understandng the pharmacology of Smoothened
Team leader
Paweł Kozielewicz
Assistant ProfessorLouise Andersson
Affiliated to ResearchAlumni
Alexander De Rosa
Alesia Tsalikou
Choi Har Tsang
Master's and PhD projects
Carl Frerik-Bowin thesis cover 2021
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2021
Doctoral thesis Carl- Fredrik Bowin (2021-11-12)
“WNT/Frizzled signaling – Illuminating the road towards pathway selectivity”
Shane C. Wright
Jana Valnohova
2018
Doctoral thesis Jana Valnohova (2018-11-09)
Belma Hot
2017
Doctoral thesis Belma Hot (2017-04-28)
"Molecular aspects of WNT/Frizzled signalling in brain angiogenesis"
Elisa Arthofer
Doctoral thesis Elisa Arthofer (2017-03-24)
Katerina Straková
Doctoral thesis Katerina Straková
"Interaction of Class Frizzled receptors with G proteins and Dishevelled"
Julian Petersen
2016
Doctoral thesis Julian Petersen (2016-01-29)
"Structural and functional analysis of WNT receptors : with emphasis on FZD6"
Jacomijn Dijksterhuis
2015
Doctoral thesis Jacomijn Dijksterhuis (2015-03-06)
"WNT/FZD signaling : an odyssey from molecular pharmacology to brain (patho)physiology"
Michaela Kilander
2013
Doctoral thesis Michaela Kilander (2013-09-06)
Carina Halleskog
Doctoral thesis Carina Halleskog (2013-06-14)
"WNT signaling in microglia : WNTs as novel regulators of microglia"
Frand Brand
2007
Doctoral thesis Frand Brand (2007-10-31)
"Agonist-induced Signaling and Endocytosis of the Adenosine A2A Receptor"
Gunnar Schulte
2002
Doctoral thesis Gunnar Schulte (2002-11-08)
"Adenosine receptor signaling and the activation of mitogen-activated protein kinases"
Vacant positions
I would be happy to assist with applications for external support in form of postdoctoral or PhD student fellowships.
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.