Gsk-3Β Phosphorylation Of Cytoplasmic Dynein Reduces Ndel1 Binding To Intermediate Chains And Alters Dynein Motility

Keywords

Axon transport; Centrosome; Cytoplasmic dynein; Insulin; Ndel1/Nde1; Retrograde transport

Abstract

Glycogen synthase kinase 3 (GSK-3) has been linked to regulation of kinesin-dependent axonal transport in squid and flies, and to indirect regulation of cytoplasmic dynein. We have now found evidence for direct regulation of dynein by mammalian GSK-3β in both neurons and non-neuronal cells. GSK-3β coprecipitates with and phosphorylates mammalian dynein. Phosphorylation of dynein intermediate chain (IC) reduces its interaction with Ndel1, a protein that contributes to dynein force generation. Two conserved residues, S87/T88 in IC-1B and S88/T89 in IC-2C, have been identified as GSK-3 targets by both mass spectrometry and site-directed mutagenesis. These sites are within an Ndel1-binding domain, and mutation of both sites alters the interaction of IC's with Ndel1. Dynein motility is stimulated by (i) pharmacological and genetic inhibition of GSK-3β, (ii) an insulin-sensitizing agent (rosiglitazone) and (iii) manipulating an insulin response pathway that leads to GSK-3β inactivation. Thus, our study connects a well-characterized insulin-signaling pathway directly to dynein stimulation via GSK-3 inhibition.

Publication Date

9-1-2015

Publication Title

Traffic

Volume

16

Issue

9

Number of Pages

941-961

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1111/tra.12304

Socpus ID

84939771192 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84939771192

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