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HEIDELBERG UNIVERSITY

Walter Nickel 
Unconventional Protein Secretion

Groupleader: Walter Nickel

Our lab investigates unconventional mechanisms of protein secretion from mammalian cells. Our primary model cargo protein is Fibroblast Growth Factor 2 (FGF2; Fig. 1), a potent mitogen involved in tumor-induced angiogenesis.





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 with the phosphoinositide PI(4,5)P2 at the inner leaflet and heparan sulfate proteoglycans at the outer leaflet of plasma membranes.  FGF2 secretion from cells further depends on FGF2 being properly folded during all stages of membrane translocation.  Finally, tyrosine phosphorylation of FGF2 was found to regulate the overall process of FGF2 secretion.





Fig. 2: The unconventional secretory pathway of FGF2

Current research goals in the lab include the analysis of the molecular mechanism by which tyrosine phosphorylation affects FGF2 secretion. Furthermore, a major goal is to understand how FGF2 physically traverses the plasma membrane, a process that involves FGF2 oligomerization and the formation of lipidic membrane pores. These studies are likely to be relevant 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 that may lead to the development of a novel class of anti-angiogenic drugs for cancer therapy.



For further reading please download the review articles (download pdf) below.

Nickel and Seedorf 2008 Annu Rev Cell Dev Biol.pdf
Nickel and Rabouille 2009 Nat Rev Mol Cell Bio.pdf
Nickel 2011 Traffic.pdf
Nickel and Rabouille 2012 J Cell Sci.pdf
Nickel and Steringer 2014 J Mol Biol.pdf

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