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First published online 15 August 2006
doi: 10.1242/jcs.03104

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Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase III ß protects from dephosphorylation and stabilizes lipid kinase activity

Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany

^* Author for correspondence (e-mail: angelika.hausser{at}izi.uni-stuttgart.de)

Accepted 16 June 2006

Phosphatidylinositol-4-kinase-IIIß (PI4KIIIß) is activated at the Golgi compartment by PKD-mediated phosphorylation. Subsequent mechanisms responsible for continuous PtdIns(4)P production at Golgi membranes and potential interaction partners of activated PI4KIIIß are unknown. Here we identify phosphoserine/-threonine binding 14-3-3 proteins as novel regulators of PI4KIIIß activity downstream of this phosphorylation. The PI4KIIIß-14-3-3 interaction, evident from GST pulldowns, co-immunoprecipitations and bimolecular fluorescence complementation, was augmented by phosphatase inhibition with okadaic acid. Binding of 14-3-3 proteins to PI4KIIIß involved the PKD phosphorylation site Ser294, evident from reduced 14-3-3 binding to a S294A PI4KIIIß mutant. Expression of dominant negative 14-3-3 proteins resulted in decreased PI4KIIIß Ser294 phosphorylation, whereas wildtype 14-3-3 proteins increased phospho-PI4KIIIß levels. This was because of protection of PI4KIIIß Ser294 phosphorylation from phosphatase-mediated dephosphorylation. The functional significance of the PI4KIIIß-14-3-3 interaction was evident from a reduction of PI4KIIIß activity upon dominant negative 14-3-3 protein expression. We propose that 14-3-3 proteins function as positive regulators of PI4KIIIß activity by protecting the lipid kinase from active site dephosphorylation, thereby ensuring a continuous supply of PtdIns(4)P at the Golgi compartment.

Key words: PI4KIIIß, 14-3-3 proteins, Phosphorylation, Golgi complex, BiFC

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