A divergent canonical WNT-signaling pathway regulates microtubule dynamics: dishevelled signals locally to stabilize microtubules.
Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta). In the canonical WNT pathway, the negative regulator Axin forms a complex with beta-catenin and GSK-3beta, resulting in beta-catenin degradation. Inhibition of GSK-3beta by DVL increases beta-catenin ... stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3beta through a transcription- and beta-catenin-independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3beta-mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3beta, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, COS Cells, Cell Line, Cercopithecus aethiops, Cerebellum, Glycogen Synthase Kinase 3, Humans, Mice, Microtubules, Neurons, Phosphoproteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Signal Transduction, Transfection, Wnt Proteins
Adaptor Proteins, Signal Transducing, Animals, Animals, Newborn, COS Cells, Cell Line, Cercopithecus aethiops, Cerebellum, Glycogen Synthase Kinase 3, Humans, Mice, Microtubules, Neurons, Phosphoproteins, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Signal Transduction, Transfection, Wnt Proteins
J. Cell Biol.
Date: Jan. 19, 2004
PubMed ID: 14734535
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