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The Journal of Neuroscience, June 1, 2001, 21(11):3764-3770

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

Yi-Ping Hsueh^{1, 2}, Anne M. Roberts³, Manuela Volta³, Morgan Sheng², and Roland G. Roberts³

¹ Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, 115, Republic of China, ² Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and ³ Division of Medical and Molecular Genetics, Guy's, King's, and St. Thomas's Medical School, London SE1 9RT, United Kingdom

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.

Key words: NF1; RasGAP; postsynaptic density; axon; yeast two-hybrid analysis; CASK/LIN-2

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21113764-07$05.00/0

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