Binding of the Receptor Tyrosine Kinase TrkB to the Neural Cell Adhesion Molecule (NCAM) Regulates Phosphorylation of NCAM and NCAM-dependent Neurite Outgrowth

Galina Dityateva,Claus Schafer-Nielsen,Melitta Schachner,Mei-Fang Xiao,Ralf Kleene,Claudia Friedrich,Claas Cassens

doi:10.1074/jbc.m110.114835

Abstract

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.

Highlights

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 [2,3,4,5,6]
Our present study has revealed a direct association of the neural cell adhesion molecule NCAM and the tyrosine receptor kinase TrkB
The functional relationship between TrkB and NCAM is evidenced by the ability of TrkB, in the presence of its ligand brain-derived neurotrophic factor (BDNF), to enhance tyrosine phosphorylation of NCAM

Summary

Introduction

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 [2,3,4,5,6]. 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 [7,8,9,10,11,12,13].

Results

Conclusion