Bipartite Interaction between Neurofibromatosis Type I Protein (Neurofibromin) and Syndecan Transmembrane Heparan Sulfate Proteoglycans

Abstract

The neurofibromatosis type 1 (NF1) gene encodes a large tumor suppressor protein (neurofibromin). Although it is known to possess Ras GTPase-activating protein (GAP) activity, the cellular role of neurofibromin remains unclear. Here we used yeast two-hybrid screening to identify neurofibromin-interacting proteins. Syndecan-2, a transmembrane heparan sulfate proteoglycan (HSPG), was isolated as a binding partner for two distinct regions of the neurofibromin protein. We subsequently found that neurofibromin can bind all four mammalian syndecans. NF1 interaction requires the transmembrane domain and a membrane-proximal region of the cytoplasmic tail of syndecan, but not the C terminus of syndecan known to bind to CASK, a membrane-associated guanylate kinase (MAGUK). Neurofibromin, syndecans, and CASK have overlapping subcellular distributions in axons and synapses of neurons, as shown by biochemical fractionation and immunostaining. Moreover, neurofibromin exists in a complex with syndecan and CASK in vivo, as evidenced by their coimmunoprecipitation from rat brain. Our findings suggest that interaction with different members of the syndecan family may be a mechanism for localizing neurofibromin to specialized domains of the plasma membrane.

Distinct Functional Domains of Neurofibromatosis Type 1 Regulate Immediate versus Long-Term Memory Formation

“…Interestingly, the NF1 protein presents a unique case of having distinct regions governing two independent steps of an important cognitive process. These NF1 protein regions that are involved in different phases of learning and memory contain different types of post-translational modification sites, such as phosphorylation sites for protein kinase A and protein kinase C (Mangoura et al, 2006), and binding sites for proteins such as syndecan (Hsueh et al, 2001). It will be interesting to investigate the role that these sites play in governing the behavioral outputs assayed in this report to find out the exact mechanisms and pathways that govern the distinct behaviors of learning and memory.…”

Valosin-containing protein and neurofibromin interact to regulate dendritic spine density

“…It acts downstream of syndecan-2, a synaptic heparan sulfate proteoglycan, in the regulation of dendritic spine formation (9). Neurofibromin interacts with syndecan-2 (22) and activates the PKA-Enabled/vasodilator-stimulated phosphoprotein (PKA-Ena/VASP) pathway to promote actin polymerization and bundle formation (9). Interestingly, although the PKA pathway is essential for dendritic spine formation, activation of PKA alone is not sufficient for the process (9), possibly due to the involvement of multiple downstream pathways of neurofibromin in spinogenesis.…”

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

“…Syndecan-2, a synaptic heparan sulfate proteoglycan, regulates synapse formation and dendritic arborization through various downstream mediators [12,52] . For syndecan-2-mediated synapse formation and maintenance, both neurofibromin and CASK protein complexes are required [52][53][54] . Sarm1 is essential for syndecan-2-regulated dendritic arborization.…”