Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway.
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.
Lin
Yi-Ling
YL
Faculty of Life Sciences, Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Lei
Ya-Ting
YT
Hong
Chen-Jei
CJ
Hsueh
Yi-Ping
YP
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000502:physiology / Q000648:ultrastructure*; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D025542:Neurofibromin 1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000502:physiology / Q000648:ultrastructure*; D015398:Signal Transduction; D053669:Syndecan-2 / Q000737:chemistry / Q000502:physiology*
D004268:DNA-Binding Proteins; C092744:ENA-VASP proteins; D025542:Neurofibromin 1; D053669:Syndecan-2; D017868:Cyclic AMP-Dependent Protein Kinases