The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism.
Myelin-derived Nogo-A protein limits axonal growth after CNS injury. One domain binds to the Nogo-66 receptor to inhibit axonal outgrowth, whereas a second domain, Amino-Nogo, inhibits axonal outgrowth and cell adhesion through unknown mechanisms. Here, we show that Amino-Nogo inhibition depends strictly on the composition of the extracellular matrix, suggesting that Amino-Nogo inhibits the function of certain integrins. Amino-Nogo inhibition can be partially overcome by antibodies that activate integrin beta1 or by the addition of Mn2+, an integrin activator. Furthermore, Amino-Nogo reduces focal adhesion kinase activation by fibronectin. Analysis of various cell lines reveals that alpha(v)beta3, alpha5, and alpha4 integrins are sensitive to Amino-Nogo, but alpha6 integrin is not. Both alpha(v) and alpha5 integrins have widespread expression in adult brain and are found in axonal growth cones. Thus, inhibition of integrin signaling by Amino-Nogo contributes to the failure of CNS axon regeneration.
Hu
Fenghua
F
Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Strittmatter
Stephen M
SM
D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D016466:CHO Cells; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology*; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D006131:Growth Inhibitors / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D019169:Jurkat Cells; D051379:Mice; D009185:Myelin Proteins / Q000737:chemistry / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology; D000070798:Nogo Proteins; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats
D006131:Growth Inhibitors; D016023:Integrins; D009185:Myelin Proteins; D000070798:Nogo Proteins; D010446:Peptide Fragments; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat