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First published online February 23, 2005
doi: 10.1242/10.1242/jcs.01697

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Glycogen synthase kinase-3ß phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons

Niraj Trivedi^1,*, Phil Marsh², Robert G. Goold¹, Alison Wood-Kaczmar¹ and Phillip R. Gordon-Weeks^1,

¹ The MRC Centre for Developmental Neurobiology, New Hunts House, Guy's Campus, King's College London, London SE1 1UL, UK
² Molecular Biology Unit, New Hunts House, Guy's Campus, King's College London, London SE1 1UL, UK

Author for correspondence (e-mail: phillip.gordon-weeks{at}kcl.ac.uk)

Accepted 30 December 2004

Recent experiments show that the microtubule-associated protein (MAP) 1B is a major phosphorylation substrate for the serine/threonine kinase glycogen synthase kinase-3ß (GSK-3ß) in differentiating neurons. GSK-3ß phosphorylation of MAP1B appears to act as a molecular switch regulating the control that MAP1B exerts on microtubule dynamics in growing axons and growth cones. Maintaining a population of dynamically unstable microtubules in growth cones is important for axon growth and growth cone pathfinding. We have mapped two GSK-3ß phosphorylation sites on mouse MAP1B to Ser1260 and Thr1265 using site-directed point mutagenesis of recombinant MAP1B proteins, in vitro kinase assays and phospho-specific antibodies. We raised phospho-specific polyclonal antibodies to these two sites and used them to show that MAP1B is phosphorylated by GSK-3ß at Ser1260 and Thr1265 in vivo. We also showed that in the developing nervous system of rat embryos, the expression of GSK-3ß phosphorylated MAP1B is spatially restricted to growing axons, in a gradient that is highest distally, despite the expression of MAP1B and GSK-3ß throughout the entire neuron. This suggests that there is a mechanism that spatially regulates the GSK-3ß phosphorylation of MAP1B in differentiating neurons. Heterologous cell transfection experiments with full-length MAP1B, in which either phosphorylation site was separately mutated to a valine or, in a double mutant, in which both sites were mutated, showed that these GSK-3ß phosphorylation sites contribute to the regulation of microtubule dynamics by MAP1B.

Key words: Microtubules, Microtubule-associated protein 1B, Glycogen synthase kinase-3ß

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