Groupleader: Walter Nickel
Walter Nickel
Unconventional Protein Secretion
Research
Our lab investigates unconventional mechanisms of protein secretion from mammalian cells. Our primary model cargo protein is Fibroblast Growth Factor 2 (FGF2), a potent mitogen involved in tumor-induced angiogenesis (Fig.1):
Fig. 1: Cis elements in FGF2 required for unconventional secretion from tumor cells.
As illustrated below (Fig. 2), unconventional secretion of FGF2 occurs by direct translocation across plasma membranes, a process that involves sequential interactions of FGF2 with ATP1A1, Tec kinase and the phosphoinositide PI(4,5)P2 at the inner leaflet of the plasma membrane. The interaction with PI(4,5)P2 causes FGF2 to oligomerize and to insert into the plasma membrane forming a toroidal pore. Membrane inserted FGF2 oligomers are believed to serve as translocation intermediates that are disassembled by heparan sulfate proteoglycans at the outer leaflet of plasma membranes. This process results in directional translocation of FGF2 from the cytoplasm into extracellular space.
Fig. 2: The unconventional secretory pathway of FGF2
Current research goals in the lab relate to the spatio-temporal coordination of FGF2 secretion in living cells, the analysis of the molecular mechanism by which FGF2 physically traverses the plasma membrane and the relevance of this process for other unconventional secretory proteins such as HIV Tat. Finally, the molecular mechanism of FGF2 secretion is used in the lab to develop inhibitors of this process with great potential for the development of drugs for cancer therapy that block the function of FGF2 as a tumor cell survival factor.
For further reading please download the review articles (download pdf) below.
Sparn-Meyer-Saleppico and Nickel 2022-TIBS.pdf
Palotta and Nickel 2020 JCS.pdf
Dimou and Nickel 2018 Curr. Biol.pdf
La Venuta et al 2015 JBC.pdf
Nickel and Steringer 2014 J Mol Biol.pdf
Nickel and Rabouille 2012 J Cell Sci.pdf
Nickel 2011 Traffic.pdf
Nickel and Rabouille 2009 Nat Rev Mol Cell Bio.pdf
Nickel and Seedorf 2008 Annu Rev Cell Dev Biol.pdf
CV
| 2024 - | Scientific Cofounder and Key Advisor Protein Engineering at Cycuria Therapeutics (cycuria.com) |
| 2024 - 2028 | Vice Speaker of the DFG Collaborative Research Center SFB/TRR 186 Heidelberg/Berlin: Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission |
| 2021 - 2024 | Managing Director of the Heidelberg University Biochemistry Center (BZH) |
| 2019 - | Dean of Studies of the Bachelor and Master programs in Biochemistry at Heidelberg University; Board member of the Faculty of Biosciences at Heidelberg University |
| 2016 - 2024 | Speaker and Founding Chair of the DFG Collaborative Research Center SFB/TRR 186 Heidelberg/Berlin: Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission |
| 2010 - 2015 | Speaker of the DFG Graduate School GRK1188 "Quantitative Analysis of Dynamic Processes in Membrane Transport and Translocation” at Heidelberg University |
| 2004 - | Professor of Biochemistry at Heidelberg University Biochemistry Center (BZH) Faculty of Biosciences |
| 2001 - 2004 | Principal Investigator at Heidelberg University Biochemistry Center (BZH) |
| 2001 | Venia legendi in Biochemistry (appointment as University Lecturer), Medical Faculty, University of Heidelberg, Germany |
| 1997-2000 | Post-doctoral research fellow (supported by a Feodor Lynen fellowship from the Alexander von Humboldt foundation and a fellowship from the Human Frontiers Science Program) in the laboratory of Prof. Dr. James E. Rothman, Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, U.S.A. |
| 1994-1997 | Post-doctoral research fellow (supported by a fellowship from the German Research Foundation) in the laboratory of Prof. Dr. Felix T. Wieland, Institute for Biochemistry I, University of Heidelberg, Germany |
| 1994 | Graduation (Dr. rer. nat.; Georg August Universität Göttingen) |
| 1991-1994 | University of Göttingen, Germany, Department for Clinical Biochemistry (Laboratory of Prof. Dr. Hans-Dieter Söling) |
| 1991 | Diploma in Biology (Georg August Universität Göttingen) |
| 1990-1991 | Max Planck Institute for Experimental Medicine, Department for Chemistry, Göttingen, Germany (Laboratory of Prof. Dr. Frank Grosse) |
| 1988-1989 | Max Planck Institute for Experimental Medicine, Department for Chemistry, Göttingen, Germany (Laboratory of Prof. Dr. Fritz Eckstein) |
| 1985-1990 | University of Göttingen, Program of Study: Biology Major: Biochemistry, Minor: Microbiology, Organic Chemistry |
Lab Members
Third row, from left to right: Julia Steringer (Postdoc), Jutta Worsch (Technical Assistant), Walter Nickel, Sabine Wegehingel (Technical Assistant), Fabio Lolicato (as of Dec 1, 2023 PI at BZH)
Second row, from left to right: Margot Ruland (Adminstrative Assistant SFB/TRR 186), Anke Heymann (Administrative Assistant), Ali Lashkari (PhD Student), Hans-Michael Müller (Senior Postdoc), Manpreet Kaur (Shared PhD Student with Fabio Lolicato), Daniel Beyer (PhD Student)
First row, from left to right: Suvarnan Selliah (Shared PhD Student with Fabio Lolicato), Jaime Fernandez Sobaberas (PhD Student), Ana Marija Knez (PhD Student)
Adminstrative Assistant
Lab:Room 309 / Phone: +49 6221 54-4160
Mail:anke.heymann@bzh.uni-heidelberg.de
Adminstrative Assistant (SFB/TRR 186)
Lab:Room 307 / Phone: +49 6221 54-4491
Mail:margot.ruland@bzh.uni-heidelberg.de
PhD student
Lab:Room 323
/ Phone: +49 6221 54-4746
Mail:daniel.beyer@bzh.uni-heidelberg.de
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PhD student
Lab:Room 322
/ Phone: +49 6221 54-5428
Mail:jaime.fernandez-sobaberas@bzh.uni-heidelberg.de
PhD student
Lab:Room 322
/ Phone: +49 6221 54-5428
Mail:manpreet.kaur@bzh.uni-heidelberg.de
PhD student
Lab:Room 321
/ Phone: +49 6221 54-4746
Mail:ana-marija.knez@bzh.uni-heidelberg.de
PhD student
Lab:Room 321
/ Phone: +49 6221 54-5427
Mail:ali.lashkari@bzh.uni-heidelberg.de
staff scientist
Lab:Room 322
/ Phone: +49 6221 54-5428
Office:Room 306
/ Phone: +49 6221 54-4180
Mail:hans-michael.mueller@bzh.uni-heidelberg.de
PhD student
Lab:Room 321
/ Phone: +49 6221 54-5427
Mail:suvarnan.selliah@bzh.uni-heidelberg.de
postdoc
Lab:Room 321
/ Phone: +49 6221 54-5427
Mail:julia.steringer@bzh.uni-heidelberg.de
TA
Lab:Room 322
/ Phone: +49 6221 54-5428
Office:Room 306
/ Phone: +49 6221 54-4180
Mail:sabine.wegehingel@bzh.uni-heidelberg.de
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TA
Lab:Room 321
/ Phone: +49 6221 54-5427
Mail:jutta.worsch@bzh.uni-heidelberg.de
Publications
Key publications
Lolicato F, Steringer JP, Saleppico R, Beyer D, Fernandez-Sobaberas J, Unger S, Klein S, Riegerová P, Wegehingel S, Müller HM, Freund C, Hof, M, Šachl R, Chlanda P, Vattulainen I, and Nickel W (2023) Disulfide bridge-dependent dimerization triggers FGF2 membrane translocation into the extracellular space. eLife 88579
Lolicato F, Saleppico R, Griffo A, Meyer A, Scollo F, Pokrandt B, Müller HM, Ewers H, Hähl H, Fleury JB, Seemann R, Hof M, Brügger B, Jacobs K, Vattulainen I, Nickel W (2022) Cholesterol promotes clustering of PI(4,5)P2 driving unconventional secretion of FGF2. J Cell Biol e202106123
Sparn C, Dimou E, Meyer A, Saleppico R, Wegehingel S, Gerstner M, Klaus S, Ewers H, Nickel W (2022) Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2. eLife e75545
Legrand C, Saleppico R, Sticht J, Lolicato F, Müller HM, Wegehingel S, Dimou E, Steringer JP, Ewers E, Vattulainen I, Freund C, Nickel W (2020) The Na,K-ATPase acts upstream of phosphoinositide PI(4,5)P2 facilitating unconventional secretion of Fibroblast Growth Factor 2. Commun Biol 3:141
Dimou E, Cosentino K, Platonova E, Ros U, Sadeghi M, Kashyap P, Katsinelos T, Wegehingel S, Noé F, García-Sáez AJ, Ewers H, Nickel W (2019) Single event visualization of unconventional secretion of FGF2. J Cell Biol 218:683-699
Katsilenos T, Zeitler M, Dimou E, Karakatsani A, Müller HM, Nachman E, Steringer JP, Ruiz de Almodovar C, Nickel W#, Jahn TR#(2018) Unconventional secretion mediates the trans-cellular spreading of Tau. Cell Reports 23:2039-2055 (# corresponding authors)
Steringer JP, Lange S, Čujová S, Šachl R, Poojari C, Lolicato F, Beutel O, Müller HM, Unger S, Coskun Ü, Honigmann A, Vattulainen I, Hof M, Freund C, Nickel W (2017) Key steps in unconventional secretion of fibroblast growth factor 2 reconstituted with purified components. eLife e28985
Müller HM, Steringer JP, Wegehingel S, Bleicken S, Münster M, Dimou E, Unger S, Weidmann G, Andreas H, García-Sáez AJ, Wild K, Sinning I, Nickel W (2015) Formation of disulfide bridges drives oligomerization, membrane pore formation, and translocation of fibroblast growth factor 2 to cell surfaces. J Biol Chem 290:8925-8937
Steringer JP, Bleicken S, Andreas H, Zacherl S, Laussmann M, Temmerman K, Contreras FX, Bharat TA, Lechner J, Müller HM, Briggs JA, García-Sáez AJ, Nickel W (2012) Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]-dependent oligomerization of fibroblast growth factor 2 (FGF2) triggers the formation of a lipidic membrane pore implicated in unconventional secretion.
J Biol Chem 287:27659-27669
Ebert AD, Laussmann M, Wegehingel S, Kaderali L, Erfle H, Reichert J, Lechner J, Beer HD, Pepperkok R, Nickel W (2010) Tec-kinase-mediated phosphorylation of fibroblast growth factor 2 is essential for unconventional secretion. Traffic 11:813-826
Zehe C, Engling A, Wegehingel S, Schäfer T, Nickel W (2006) Cell-surface heparan sulfate proteoglycans are essential components of the unconventional export machinery of FGF-2.
Proc. Natl. Acad. Sci. U.S.A. 103:15479-15484
Seelenmeyer C, Wegehingel S, Tews I, Künzler M, Aebi M, Nickel W (2005) Cell surface counter receptors are essential components of the unconventional export machinery of galectin-1.
J. Cell Biol. 17:373-381
Reviews on unconventional protein secretion
Sparn C, Meyer, A, Saleppico R, and Nickel W (2022) Unconventional secretion mediated by direct protein self-translocation across the plasma membranes of mammalian cells.
Trends Biochem Sci 47:699-709
Lolicato F and Nickel W (2022) A role for liquid-ordered plasma membrane nanodomains coordinating the unconventional secretory pathway of Fibroblast Groth Factor 2.
Front Cell Dev Biol 10:864257
Pallotta MT and Nickel W (2020) FGF2 and IL-1β: Explorers of unconventional secrtory pathways.
J Cell Sci 133(21):jcs250449
Dimou E and Nickel W (2018) Unconventional mechanisms of eukaryotic protein secretion.
Curr Biol 28:R406-R410
Complete list of publications:
Walter Nickel at PubMed
Collaborations
Petr Chlanda, BioQuant Heidelberg
Christian Freund, FU Berlin
Helge Ewers, FU Berlin
Ana Garcia-Saez, Tübingen
Martin Hof, Prague
Ilpo Vattulainen, Helsinki
Helmut Thomas, Cyclenium Pharma, Montreal
Coordinating functions
Coordinating functions:
2021-
Managing Director of Heidelberg University Biochemistry Center
2019-
Dean of studies of the Bachelor and Master programmes in Biochemistry (Faculty of Biosciences, Heidelberg University)
2016-
Speaker and founding chair of the DFG Collaborative Research Centre SFB/TRR 186 Heidelberg/Berlin; "Molecular switches in the spatio-temporal control of cellular sognal transmission"
2011-2014
Chair of the DFG Graduate School "Quantitative Analysis of Dynamic Processes in
Membrane Transport and Translocation" (GRK 1188)
2009-2012
Chair of the EuroMembrane Programme of the European Science Foundation (ESF)
2005-2010
Vice-Chair of the DFG Graduate School "Quantitative Analysis of Dynamic Processes in Membrane Transport and Translocation" (GRK 1188)
Funding
Past and current funding of our laboratory came from the German Research Foundation (DFG), the European Science Foundation (ESF), the Federal Ministry of Education and Research (BMBF), the Baden-Württemberg Foundation, the Peter and Traudl Engelhorn Foundation and the Boehringer Ingelheim Fonds (BIF).
Open Positions
Young scientists with a background in biochemistry, biophysics or molecular cell biology, being interested in doing a PhD thesis or post-doctoral work in our research group at BZH are encouraged to get in touch with Walter Nickel at walter.nickel@bzh.uni-heidelberg.de
Contact
der Universität Heidelberg (BZH)
Im Neuenheimer Feld 328
69120 Heidelberg
