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Published online June 4, 2007
doi:10.1083/jcb.200608121
The Journal of Cell Biology, Vol. 177, No. 5, 829-841
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Lin et al.
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Article

 Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin–PKA–Ena/VASP pathway

Yi-Ling Lin1,4, Ya-Ting Lei2,4, Chen-Jei Hong3,4, and Yi-Ping Hsueh1,2,3,4

1 Faculty of Life Sciences, Institute of Genome Sciences, and 2 Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan
3 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
4 Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan

Correspondence to Yi-Ping Hsueh: yph{at}gate.sinica.edu.tw

Syndecan-2 induced filopodia before spinogenesis; therefore, filopodia formation was used here as a model to study the early downstream signaling of syndecan-2 that leads to spinogenesis. Screening using kinase inhibitors indicated that protein kinase A (PKA) is required for syndecan-2–induced filopodia formation in both human embryonic kidney cells and hippocampal neurons. Because neurofibromin, a syndecan-2–binding partner, activates the cyclic adenosine monophosphate pathway, the role of neurofibromin in syndecan-2–induced filopodia formation was investigated by deletion mutant analysis, RNA interference, and dominant-negative mutant. The results showed that neurofibromin mediates the syndecan-2 signal to PKA. Among actin-associated proteins, Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP) were predicted as PKA effectors downstream of syndecan-2, as Ena/VASP, which is activated by PKA, induces actin polymerization. Indeed, when the activities of Ena/VASP were blocked, syndecan-2 no longer induced filopodia formation. Finally, in addition to filopodia formation, neurofibromin and Ena/VASP contributed to spinogenesis. This study reveals a novel signaling pathway in which syndecan-2 activates PKA via neurofibromin and PKA consequently phosphorylates Ena/VASP, promoting filopodia and spine formation.

Abbreviations used in this paper: CASK, calcium/CaM-dependent serine protein kinase; DIV, day in vitro; Ena, Enabled; EVL, Ena-VASP–like; FSK, forskolin; HEK, human embryonic kidney; Mena, mammalian enabled; NF1, neurofibromatosis type 1; PI3K, phosphatidylinositol 3-kinase; shRNA, small hairpin RNA; VASP, vasodilator-stimulated phosphoprotein.


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