A novel gene expression pathway regulated by nuclear phosphoinositides

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Introduction

Phosphatidylinositol phosphate (PIP) kinases are responsible for the production of the lipid signaling molecule phosphatidylinositol 4,5-bisphosphate, PI4,5P2. PI4,5P2 can directly affect the function of an array of signal transduction pathways by interactions with PI4,5P2 effectors. PIP kinases modulate PI4,5P2 sensitive pathways by controlling the generation of PI4,5P2 through interactions between PIP kinases and protein partners which target the PIP kinases to specific sub-cellular compartments. In addition, the protein partners are often themselves PI4,5P2 regulated proteins. PIP kinase targeting in this manner allows for the spatial and temporal generation of PI4,5P2 to affect specific signaling pathways. Identification of these protein partners has allowed for the determination of many molecular mechanisms of PI4,5P2 signaling. Recently, a nuclear speckle targeted non-canonical poly(A) polymerase, Star-PAP, has been defined to have a functional interaction with the type Iα PIP kinase to process select mRNAs for their 3′ end formation. Star-PAP contains a poly(A) polymerase catalytic and core domains (PAP) though it differs from the canonical PAP due to its unique domain arrangement and phosphoinositide regulation. Star-PAP is a duel specificity polymerase that harbors in vitro poly(A) polymerase activity that is stimulated by PI4,5P2, and also embodies features of Terminal Uridylyl Transferase (TUTase) in both of its domain arrangement and its in vitro ability to transfer UMP to cellular RNA including the small nuclear RNA U6. The Star-PAP complex of proteins contains a number of cleavage and polyadenylation components, an active PIPKIα capable of generating de novo PI4,5P2, and the PI4,5P2 sensitive protein kinase CKIα. CKIα can directly phosphorylate Star-PAP and, in conjunction with PIPKIα, is required for expression and maintenance of the Star-PAP target mRNA HO-1. HO-1 mRNA encodes the cytoprotective enzyme heme oxygenase-1, which is an important detoxifying enzyme involved in protection from reactive oxygen species and cellular oxidative stresses. HO-1 is upregulated in response to oxidative stress through increase in transcription, placing Star-PAP, PIPKIα and CKIα as mediators of oxidative cellular stress response. Taken together, the Star-PAP complex represents a focal point for nuclear phosphoinositide signaling where Star-PAP, PIPKIα and CKIα can synergize to regulate the 3′ end formation of select mRNAs.

Section snippets

Type I PIP kinases generate PI4,5P2 to regulate signaling events

Phosphatidylinositol phosphate (PIP) kinases are lipid kinases that function to generate phosphoinositide signaling molecules, which play critical roles throughout the life cycle of metazoans (Gardocki et al., 2005). The type I PIP kinases, PIPKIα, -β, -γ are PI-4′-phosphate 5′-kinases that synthesize the signaling molecule PI4,5P2 utilizing PI4P as a substrate (Heck et al., 2007). Over the last decade a wealth of accumulated evidence has indicated that the different phosphorylated PIs serve

PIPKIα directly interacts with a nuclear speckle localized non-canonical poly(A) polymerase, Star-PAP, and resides in complex with 3′end formation machinery components

Based on the model of PI4,5P2 signaling specificity being dependent upon its interactions with protein partners and targeting factors (Doughman et al., 2003), a yeast two-hybrid screen was established to identify PIPKIα interacting proteins to define functional roles for PIPKIα and its product PI4,5P2 nuclear signaling events. The region of PIPKIα that was responsible for its nuclear targeting was determined to be in the carboxy-terminus, amino acids 440–562, therefore this portion of the

Summary

Star-PAP is a recently identified nuclear speckle localized non-canonical poly(A) polymerase that has a functional interaction with PIPKIα, and whose activity is modulated by the PIPKIα product, PI4,5P2. Similar to other poly(A) polymerases, such as the canonical PAPα and the non-canonical GLD2 PAP, Star-PAP resides in a large complex of proteins involved in the 3′ end formation of mRNAs (Fig. 4). The Star-PAP complex shares components with the canonical PAPα complex though it contains unique

Acknowledgements

We would like to acknowledge Dr. C.A. Barlow for critical conversations in the writing process. We acknowledge the National Institutes of Health, NIH, for funding. Additionally, DLM acknowledges the American Heart Association, AHA, for funding.

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