Abstract
Nedd4-1 is a "neuronal precursor cell expressed and developmentally downregulated protein" and among the most abundant E3 ubiquitin ligases in mammalian neurons. In analyses of conventional and conditional Nedd4-1-deficient mice, we found that Nedd4-1 plays a critical role in dendrite formation. Nedd4-1, the serine/threonine kinase TNIK, and Rap2A form a complex that controls Nedd4-1-mediated ubiquitination of Rap2A. Ubiquitination by Nedd4-1 inhibits Rap2A function, which reduces the activity of Rap2 effector kinases of the TNIK family and promotes dendrite growth. We conclude that a Nedd4-1/Rap2A/TNIK signaling pathway regulates neurite growth and arborization in mammalian neurons.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Cells, Cultured
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Coculture Techniques / methods
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Endosomal Sorting Complexes Required for Transport / deficiency
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / physiology*
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology*
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Germinal Center Kinases
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Green Fluorescent Proteins / genetics
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Hippocampus
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Humans
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Membrane Potentials / genetics
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Membrane Potentials / physiology
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Mice
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Mice, Knockout
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Microglia / physiology
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Myelin Proteolipid Protein / metabolism
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Nedd4 Ubiquitin Protein Ligases
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Neurites / drug effects
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Neurites / physiology*
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Neurons / cytology*
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Patch-Clamp Techniques
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / pharmacology
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Rats
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology
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Silver Staining / methods
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Subcellular Fractions / metabolism
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Subcellular Fractions / ultrastructure
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Transfection / methods
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / physiology*
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rap GTP-Binding Proteins / genetics
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rap GTP-Binding Proteins / metabolism*
Substances
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Endosomal Sorting Complexes Required for Transport
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Germinal Center Kinases
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Myelin Proteolipid Protein
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Plp1 protein, mouse
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RNA, Small Interfering
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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NEDD4L protein, rat
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Nedd4 Ubiquitin Protein Ligases
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Nedd4 protein, human
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Nedd4 protein, rat
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Nedd4l protein, mouse
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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TNIK protein, human
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RAP2A protein, human
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rap GTP-Binding Proteins