Bipartite interaction between neurofibromatosis type I protein (neurofibromin) and syndecan transmembrane heparan sulfate proteoglycans

The neurofibromatosis type 1 (NF1) gene encodes a large tumor suppressor pr otein (neurofibromin). Although it is known to possess Ras GTPase-activatin g protein (GAP) activity, the cellular role of neurofibromin remains unclea r. Here we used yeast two-hybrid screening to identify neurofibromin-intera cting proteins. Syndecan-2, a transmembrane heparan sulfate proteoglycan (H SPG), was isolated as a binding partner for two distinct regions of the neu rofibromin protein. We subsequently found that neurofibromin can bind all f our 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 gu anylate kinase (MAGUK). Neurofibromin, syndecans, and CASK have overlapping subcellular distributions in axons and synapses of neurons, as shown by bi ochemical fractionation and immunostaining. Moreover, neurofibromin exists in a complex with syndecan and CASK in vivo, as evidenced by their coimmuno precipitation from rat brain. Our findings suggest that interaction with di fferent members of the syndecan family may be a mechanism for localizing ne urofibromin to specialized domains of the plasma membrane.