Recognition molecules and neurotrophins play important roles during development and maintenance of nervous system functions. In this study, we provide evidence that the neural cell adhesion molecule (NCAM) and the neurotrophin receptor TrkB directly interact via sequences in their intracellular domains. Stimulation of TrkB by brain-derived neurotrophic factor leads to tyrosine phosphorylation of NCAM at position 734. Mutation of this tyrosine to phenylalanine completely abolishes tyrosine phosphorylation of NCAM by TrkB. Moreover, the knockdown of TrkB in hippocampal neurons leads to a reduction of NCAM-induced neurite outgrowth. Transfection of NCAM-deficient hippocampal neurons with mutated NCAM carrying an exchange of tyrosine by phenylalanine at position 734 leads to promotion of NCAM-induced neurite outgrowth in comparison with that observed after transfection with wild-type NCAM, whereas a reduction of neurite outgrowth was observed after transfection with mutated NCAM, which carries an exchange of tyrosine by glutamate that mimics the phosphorylated tyrosine. Our observations indicate a functional relationship between TrkB and NCAM.Development and maintenance of nervous system functions depend on molecular cues that interact with each other in morphogenetic processes, such as cell proliferation, migration, differentiation and survival, neuritogenesis, and synaptogenesis, as well as in regulation of synaptic activity in the adult. Recognition molecules have been shown to play an important role in these interactions. Equally important are neurotrophic factors that regulate neuronal survival and neuritogenesis not only during development, but also in the adult, when the nervous system is under constraint to regenerate after injury and during synaptic plasticity, underlying learning and memory (1).Among the recognition molecules, the neural cell adhesion molecule (NCAM) 3 has been recognized to be a major player in neuronal cell interactions, including formation and modulation of synaptic contacts (2-6). Overlapping in some functions with NCAM, the neurotrophin receptor TrkB (receptor tyrosine kinase B), a receptor tyrosine kinase that is triggered by its ligand, the brain-derived neurotrophic factor (BDNF), regulates neuronal cell survival, neurite outgrowth, synaptogenesis, and synaptic activity (7-13). It has been suggested that NCAM via its ␣2,8-linked polysialic acid (PSA) presents BDNF to TrkB, thus concentrating the neurotrophin close to the site of its action (14, 15). On the other hand, a recent study showed that PSA removal increases the binding of BDNF to septal neurons and thereby causes an increase in choline acetyltransferase activity (16). Here we show that NCAM and TrkB directly interact with each other via their intracellular domains and that the interaction of the two proteins regulates NCAM-mediated neurite outgrowth. Furthermore, TrkB mediates the tyrosine phosphorylation of NCAM, thus playing a regulatory role in NCAM-mediated neurite outgrowth. EXPERIMENTAL PROCEDURESMice-C57BL/6J mice o...

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