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Sci. Signal., 8 May 2012
Vol. 5, Issue 223, p. ra36
[DOI: 10.1126/scisignal.2002495]

RESEARCH ARTICLES

Syndecan 4 Regulates FGFR1 Signaling in Endothelial Cells by Directing Macropinocytosis

Arye Elfenbein1,2, Anthony Lanahan2, Theresa X. Zhou3*, Alisa Yamasaki4*, Eugene Tkachenko5, Michiyuki Matsuda1, and Michael Simons2,6{dagger}

1 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
2 Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Weill-Cornell Medical College, New York, NY 10065, USA.
4 Harvard Medical School, Cambridge, MA 02120, USA.
5 Departments of Medicine and Physics, University of California, San Diego, La Jolla, CA 92093, USA.
6 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.

* These authors contributed equally to this work.

Abstract: Fibroblast growth factor 2 (FGF2) induces endothelial cell migration and angiogenesis through two classes of receptors: receptor tyrosine kinases, such as FGF receptor 1 (FGFR1), and heparan sulfate proteoglycans, such as syndecan 4 (S4). We examined the distinct contributions of FGFR1 and S4 in shaping the endothelial response to FGF2. S4 determined the kinetics and magnitude of FGF2-induced mitogen-activated protein kinase (MAPK) signaling by promoting the macropinocytosis of the FGFR1-S4-FGF2 signaling complex. Internalization of the S4 receptor complex was independent of clathrin and dynamin, proceeded from lipid raft–enriched membranes, and required activation of the guanosine triphosphatases RhoG and Rab5. Genetic knockout of S4, disruption of S4 function, or inhibition of Rab5 led to increased endocytosis and MAPK signaling. These data define the mechanism by which FGFR1 and S4 coordinate downstream signaling upon FGF2 stimulation: FGFR1 initiates MAPK signaling, whereas S4-dependent FGFR1 macropinocytosis modulates the kinetics of MAPK activation. Our studies identify S4 as a regulator of MAPK signaling and address the question of how distinct classes of FGFRs individually contribute to signal transduction in endothelial cells.

{dagger} To whom correspondence should be addressed. E-mail: michael.simons{at}yale.edu

Citation: A. Elfenbein, A. Lanahan, T. X. Zhou, A. Yamasaki, E. Tkachenko, M. Matsuda, M. Simons, Syndecan 4 Regulates FGFR1 Signaling in Endothelial Cells by Directing Macropinocytosis. Sci. Signal. 5, ra36 (2012).

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