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J. Biol. Chem., Vol. 283, Issue 13, 8678-8686, March 28, 2008

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Coordinated Activation of the Nuclear Ubiquitin Ligase Cul3-SPOP by the Generation of Phosphatidylinositol 5-Phosphate^*

Matthew W. Bunce, Igor V. Boronenkov, and Richard A. Anderson¹

From the Department of Pharmacology and the Biomolecular Chemistry Graduate Program, University of Wisconsin, Madison, Wisconsin 53706

Phosphoinositide signaling pathways regulate numerous processes in eukaryotic cells, including migration, proliferation, and survival. The regulatory lipid phosphatidylinositol 4,5-bisphosphate is synthesized by two distinct classes of phosphatidylinositol phosphate kinases (PIPKs), the type I and II PIPKs. Although numerous physiological functions have been identified for type I PIPKs, little is known about the functions and regulation of type II PIPK. Using a yeast two-hybrid screen, we identified an interaction between the type IIβ PIPK isoform (PIPKIIβ) and SPOP (speckle-type POZ domain protein), a nuclear speckle-associated protein that recruits substrates to Cul3-based ubiquitin ligases. PIPKIIβ and SPOP interact and co-localize at nuclear speckles in mammalian cells, and SPOP mediates the ubiquitylation of PIPKIIβ by Cul3-based ubiquitin ligases. Additionally, stimulation of the p38 MAPK pathway enhances the ubiquitin ligase activity of Cul3-SPOP toward multiple substrate proteins. Finally, a kinase-dead PIPKIIβ mutant enhanced ubiquitylation of Cul3-SPOP substrates. The kinase-dead PIPKIIβ mutant increases the cellular content of its substrate lipid phosphatidylinositol 5-phosphate (PI5P), suggesting that PI5P may stimulate Cul3-SPOP activity through a p38-dependent signaling pathway. Expression of phosphatidylinositol-4,5-bisphosphate 4-phosphatases that generate PI5P dramatically stimulated Cul3-SPOP activity and was blocked by the p38 inhibitor SB203580. Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKIIβ as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex.

Received for publication, December 14, 2007 , and in revised form, January 22, 2008.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1300 University Ave., Rm. 3750 MSC, Madison, WI 53706. Tel.: 608-262-3753; Fax: 608-262-1257; E-mail: raanders{at}wisc.edu.

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