Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2

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Abstract

Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is transported into the extracellular space by an unconventional secretory mechanism. Cell surface heparan sulfate proteoglycans are known to play an essential role in this process. Unexpectedly, we found that among the diverse sub-classes consisting of syndecans, perlecans, glypicans and others, Glypican-1 (GPC1) is the principle and rate-limiting factor that drives unconventional secretion of FGF2. By contrast, we demonstrate GPC1 to be dispensable for FGF2 signaling into cells. We provide first insights into the structural basis for GPC1-dependent FGF2 secretion, identifying disaccharides with N-linked sulfate groups to be enriched in the heparan sulfate chains of GPC1 to which FGF2 binds with high affinity. Our findings have broad implications for the role of GPC1 as a key molecule in tumor progression.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for various Figures being provided in a compressed zip file.

Article and author information

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Carola Sparn

Biochemistry Center, Heidelberg University, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Eleni Dimou

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4885-135X
Annalena Meyer

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.
Roberto Saleppico

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.
Sabine Wegehingel

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.
Matthias Gerstner

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.
Severina Klaus

Biochemistry Center, Heidelberg University, Heidelberg, Germany

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The authors declare that no competing interests exist.
Helge Ewers

Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3948-4332
Walter Nickel

Biochemistry Center, Heidelberg University, Heidelberg, Germany

For correspondence
walter.nickel@bzh.uni-heidelberg.de

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6496-8286

Funding

Deutsche Forschungsgemeinschaft (SFB/TRR 83 - A5)

Carola Sparn
Walter Nickel

Deutsche Forschungsgemeinschaft (SFB/TRR 186 - A1)

Eleni Dimou
Annalena Meyer
Roberto Saleppico
Helge Ewers
Walter Nickel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.