title: Specific serine-proline phosphorylation and glycogen synthase kinase 3β-directed subcellular targeting of stathmin 3/Sclip in neurons.
abstract: During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific proline-rich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3β both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3β target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3β induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.
authors.affiliation: INSERM U839, Paris F-75005, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Devaux
authors.forename: Fabienne E
authors.initials: FE
authors.lastname: Poulain
authors.forename: Véronique
authors.initials: V
authors.lastname: Devignot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lachkar
authors.forename: Theano
authors.initials: T
authors.lastname: Irinopoulou
authors.forename: André
authors.initials: A
authors.lastname: Sobel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012694:Serine / Q000737:chemistry*; D050777:Stathmin / Q000378:metabolism*
chemical_list: D050777:Stathmin; D012694:Serine; D011392:Proline; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3