Ruprecht-Karls-Universität Heidelberg
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Nickel0317 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Nickel, Walter
Application deadline:
28. Feb 2018
Start of PhD project:
1. Mar 2018

Project description:

Molecular analysis of the spatio-temporal coordination of FGF2 membrane recruitment and translocation in living cells
Fibroblast Growth Factor 2 (FGF2) is a strong mitogen promoting angiogenesis in health and disease. Under pathological conditions, FGF2 is functioning as a major activator of tumour-induced angiogenesis and also acts as a survival factor of tumour cells mediated by an autocrine signaling loop suppressing apoptosis. Despite its defined extracellular functions, FGF2 lacks a signal peptide and was shown to get exported from cells by an unconventional, ER/Golgi-independent mechanism of protein secretion. Understanding the molecular mechanism by which FGF2 is secreted from tumour cells may pave the way to develop a new class of anti-angiogenic inhibitors with a high potential to be useful in cancer therapy.
The molecular mechanism of unconventional secretion of FGF2 is based upon direct translocation across the plasma membrane. This process is initiated by the recruitment of FGF2 at the inner leaflet of the plasma membrane mediated by the phosphoinositide PI(4,5)P2. This interaction causes FGF2 to oligomerize followed by membrane insertion of oligomeric translocation intermediates. In a final step, cell surface heparan sulfate proteoglycans disassemble membrane-inserted FGF2 oligomers at the outer leaflet resulting in FGF2 translocation to the cell surface.
The goal of this project will be to analyze how FGF2 transport into the extracellular space is coordinated in space and time in livings cells. Using single molecule super-resolution TIRF microscopy, we plan to study the nanoscopic organization of the FGF2 secretion machinery with the hypothesis of discrete microdomains in the plasma membrane containing all components and functioning as specialized sites of FGF2 membrane translocation.
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.

Brough D, Pellegrin P, and Nickel W (2017) An emerging case for membrane pore formation as a common mechanism for the unconventional secretion of FGF2 and IL-1beta. J. Cell Sci 130: 3197-3202

La Venuta G, Zeitler M, Steringer JP, Müller HM, Nickel W (2015) The Startling Properties of Fibroblast Growth Factor 2: How to Exit Mammalian Cells Without a Signal Peptide at Hand? J Biol Chem. 290:27015-27020
Methods that will be used:
Single molecule super-resolution TIRF microscopy in living cells; Molecular biology and Biochemistry techniques, Retroviral transduction to generate stable cell lines with inducible protein expression
Cooperation partners:
Prof. Dr. Helge Ewers
Institut für Biochemie und Chemie, Freie Universität Berlin
Personal qualifications:
We are looking for enthusiastic students with a master degree in the life sciences and a prime interest in advanced live cell imaging techniques along with an interest in interdisciplinary studies at the interface of biochemistry, biophysics, structural biology and cell biology.