RNA Processing

Kinases in the Polyadenylation Complex

Science Signaling  06 May 2008:
Vol. 1, Issue 18, pp. ec160
DOI: 10.1126/stke.118ec160

After transcription of a gene, the abundance of a protein in a cell can be controlled through various mechanisms operating on the mRNA, including regulation of alternative splicing, polyadenylation, stability and degradation, nuclear export, and accessibility to translation factors. Star-PAP is a noncanonical poly(A) polymerase that has a proline-rich region (PRR), which splits the catalytic domain. Star-PAP functions as part of a larger macromolecular complex. However, in addition to the common proteins found in other polyadenylation complexes, the Star-PAP complex includes phosphatidylinositol-4-phosphate 5 kinase Iα (PIPKIα), and Star-PAP activity is stimulated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Gonzales et al. showed that the Star-PAP complex isolated from transfected cells also includes protein kinase activity and that Star-PAP is phosphorylated by the associated kinase. The protein kinase activity of the Star-PAP complex was inhibited by the addition of PI(4,5)P2, which led the authors to identify the kinase as casein kinase Iα (CKIα), which is known to be inhibited by PI(4,5)P2. CKIα and Star-PAP colocalized in nuclear speckles, which are a site of pre-mRNA processing, and inhibitors of CKIα blocked Star-PAP phosphorylation in vitro. Star-PAP is responsible for increasing the abundance of many mRNAs based on microarray experiments; however, CKIα and PIPKIα appear to control the targeting of Star-PAP to a subset of mRNAs involved in oxidative stress. Cells in which CKIα or PIPKIα was decreased using siRNA showed a specific decrease in the abundance of a subset of mRNAs processed by Star-PAP, including two that encode enzymes involved in the response to oxidative stress (HO-1 and NQO1), without affecting other transcripts targeted by Star-PAP. Thus, the presence of a lipid kinase and a protein kinase in the Star-PAP complex appears to target Star-PAP to specific mRNA targets and connects nuclear lipid signaling to mRNA processing.

M. L. Gonzales, D. L. Mellman, R. A. Anderson, CKIα is associated with and phosphorylates Star-PAP and is also required for expression of select Star-PAP target messenger RNAs. J. Biol. Chem. 283, 12665-12673 (2008). [Abstract] [Full Text]