Akt Phosphorylation and Nuclear Phosphoinositide Association Mediate MRNA Export and Cell Proliferation Activities by ALY

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Jun 20

PMID 18562279

Citations 53

Authors

Masashi Okada

Sang-Wuk Jang

Keqiang Ye

Affiliations

Soon will be listed here.

Abstract

Nuclear PI3K and its downstream effectors play essential roles in a variety of cellular activities including cell proliferation, survival, differentiation, and pre-mRNA splicing. Aly is a nuclear speckle protein implicated in mRNA export. Here we show that Aly is a physiological target of nuclear PI3K signaling, which regulates its subnuclear residency, cell proliferation, and mRNA export activities through nuclear Akt phosphorylation and phosphoinositide association. Nuclear Akt phosphorylates Aly on threonine-219, which is required for its interaction with Akt. Aly binds phosphoinositides, and this action is regulated by Akt-mediated phosphorylation. Phosphoinositide binding but not Akt phosphorylation dictates Aly's nuclear speckle residency. Depletion of Aly results in cell growth suppression and mRNA export reduction. Inhibition of Aly phosphorylation substantially decreases cell proliferation and mRNA export. Furthermore, disruption of phosphoinositide association with Aly also significantly reduces these activities. Thus, nuclear PI3K signaling mediates both cell proliferation and mRNA export functions of Aly.

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References

Clarke J, Letcher A, Dsantos C, Halstead J, Irvine R, Divecha N . Inositol lipids are regulated during cell cycle progression in the nuclei of murine erythroleukaemia cells. Biochem J. 2001; 357(Pt 3):905-10. PMC: 1222024. DOI: 10.1042/0264-6021:3570905. View

REED R, Magni K . A new view of mRNA export: separating the wheat from the chaff. Nat Cell Biol. 2001; 3(9):E201-4. DOI: 10.1038/ncb0901-e201. View

Gimm O, Perren A, Weng L, Marsh D, Yeh J, Ziebold U . Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am J Pathol. 2000; 156(5):1693-700. PMC: 1876937. DOI: 10.1016/S0002-9440(10)65040-7. View

York J, MAJERUS P . Nuclear phosphatidylinositols decrease during S-phase of the cell cycle in HeLa cells. J Biol Chem. 1994; 269(11):7847-50. View

Stamm S . Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome. Hum Mol Genet. 2002; 11(20):2409-16. DOI: 10.1093/hmg/11.20.2409. View

Didichenko S, Thelen M . Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles. J Biol Chem. 2001; 276(51):48135-42. DOI: 10.1074/jbc.M104610200. View

Martelli A, Manzoli L, Cocco L . Nuclear inositides: facts and perspectives. Pharmacol Ther. 2004; 101(1):47-64. DOI: 10.1016/j.pharmthera.2003.10.003. View

Torres J, Navarro S, Rogla I, Ripoll F, Lluch A, Garcia-Conde J . Heterogeneous lack of expression of the tumour suppressor PTEN protein in human neoplastic tissues. Eur J Cancer. 2001; 37(1):114-21. DOI: 10.1016/s0959-8049(00)00366-x. View

Dangi S, Cha H, Shapiro P . Requirement for phosphatidylinositol-3 kinase activity during progression through S-phase and entry into mitosis. Cell Signal. 2003; 15(7):667-75. DOI: 10.1016/s0898-6568(03)00002-0. View

10.

Ahn J, Rong R, Liu X, Ye K . PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus. EMBO J. 2004; 23(20):3995-4006. PMC: 524338. DOI: 10.1038/sj.emboj.7600392. View

11.

Lachyankar M, Sultana N, Schonhoff C, Mitra P, Poluha W, Lambert S . A role for nuclear PTEN in neuronal differentiation. J Neurosci. 2000; 20(4):1404-13. PMC: 6772384. View

12.

Ahn J, Liu X, Cheng D, Peng J, Chan P, Wade P . Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. Mol Cell. 2005; 18(4):435-45. DOI: 10.1016/j.molcel.2005.04.010. View

13.

Zenklusen D, Vinciguerra P, Strahm Y, Stutz F . The yeast hnRNP-Like proteins Yra1p and Yra2p participate in mRNA export through interaction with Mex67p. Mol Cell Biol. 2001; 21(13):4219-32. PMC: 87083. DOI: 10.1128/MCB.21.13.4219-4232.2001. View

14.

Ye K, Aghdasi B, Luo H, Moriarity J, Wu F, Hong J . Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature. 2002; 415(6871):541-4. DOI: 10.1038/415541a. View

15.

Luo M, REED R . Splicing is required for rapid and efficient mRNA export in metazoans. Proc Natl Acad Sci U S A. 1999; 96(26):14937-42. PMC: 24751. DOI: 10.1073/pnas.96.26.14937. View

16.

Anderson R, Boronenkov I, Doughman S, Kunz J, Loijens J . Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J Biol Chem. 1999; 274(15):9907-10. DOI: 10.1074/jbc.274.15.9907. View

17.

Dundr M, Misteli T . Functional architecture in the cell nucleus. Biochem J. 2001; 356(Pt 2):297-310. PMC: 1221839. DOI: 10.1042/0264-6021:3560297. View

18.

OSBORNE S, Thomas C, Gschmeissner S, Schiavo G . Nuclear PtdIns(4,5)P2 assembles in a mitotically regulated particle involved in pre-mRNA splicing. J Cell Sci. 2001; 114(Pt 13):2501-11. DOI: 10.1242/jcs.114.13.2501. View

19.

Swaminathan S, Kile A, MacDonald E, Koepp D . Yra1 is required for S phase entry and affects Dia2 binding to replication origins. Mol Cell Biol. 2007; 27(13):4674-84. PMC: 1951488. DOI: 10.1128/MCB.02052-06. View

20.

Jones S, Klinghoffer R, Prestwich G, Toker A, Kazlauskas A . PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1. Curr Biol. 1999; 9(10):512-21. DOI: 10.1016/s0960-9822(99)80235-8. View