Compartmentalized Phosphorylation of IAP by Protein Kinase A Regulates Cytoprotection

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2007 Jul 7

PMID 17612487

Citations 75

Authors

Takehiko Dohi

Fang Xia

Dario C Altieri

Affiliations

Soon will be listed here.

Abstract

Cell death pathways are likely regulated in specialized subcellular microdomains, but how this occurs is not understood. Here, we show that cyclic AMP-dependent protein kinase A (PKA) phosphorylates the inhibitor of apoptosis (IAP) protein survivin on Ser20 in the cytosol, but not in mitochondria. This phosphorylation event disrupts the binding interface between survivin and its antiapoptotic cofactor, XIAP. Conversely, mitochondrial survivin or a non-PKA phosphorylatable survivin mutant binds XIAP avidly, enhances XIAP stability, synergistically inhibits apoptosis, and accelerates tumor growth, in vivo. Therefore, differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.

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References

Altieri D . The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol. 2006; 18(6):609-15. DOI: 10.1016/j.ceb.2006.08.015. View

Cho-Chung Y, Nesterova M, Becker K, Srivastava R, Park Y, Lee Y . Dissecting the circuitry of protein kinase A and cAMP signaling in cancer genesis: antisense, microarray, gene overexpression, and transcription factor decoy. Ann N Y Acad Sci. 2002; 968:22-36. DOI: 10.1111/j.1749-6632.2002.tb04324.x. View

OConnor D, Grossman D, Plescia J, Li F, Zhang H, Villa A . Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc Natl Acad Sci U S A. 2000; 97(24):13103-7. PMC: 27185. DOI: 10.1073/pnas.240390697. View

Deng Y, Ren X, Yang L, Lin Y, Wu X . A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell. 2003; 115(1):61-70. DOI: 10.1016/s0092-8674(03)00757-8. View

Amieux P, McKnight G . The essential role of RI alpha in the maintenance of regulated PKA activity. Ann N Y Acad Sci. 2002; 968:75-95. DOI: 10.1111/j.1749-6632.2002.tb04328.x. View

Kirschner L, Carney J, Pack S, Taymans S, Giatzakis C, Cho Y . Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000; 26(1):89-92. DOI: 10.1038/79238. View

Xin M, Deng X . Protein phosphatase 2A enhances the proapoptotic function of Bax through dephosphorylation. J Biol Chem. 2006; 281(27):18859-67. DOI: 10.1074/jbc.M512543200. View

Wong W, Scott J . AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol. 2004; 5(12):959-70. DOI: 10.1038/nrm1527. View

Wright C, Duckett C . Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J Clin Invest. 2005; 115(10):2673-8. PMC: 1236691. DOI: 10.1172/JCI26251. View

10.

Kinderman F, Kim C, von Daake S, Ma Y, Pham B, Spraggon G . A dynamic mechanism for AKAP binding to RII isoforms of cAMP-dependent protein kinase. Mol Cell. 2006; 24(3):397-408. PMC: 1855097. DOI: 10.1016/j.molcel.2006.09.015. View

11.

Caldas H, Jiang Y, Holloway M, Fangusaro J, Mahotka C, Conway E . Survivin splice variants regulate the balance between proliferation and cell death. Oncogene. 2005; 24(12):1994-2007. DOI: 10.1038/sj.onc.1208350. View

12.

Griffin K, Kirschner L, Matyakhina L, Stergiopoulos S, Robinson-White A, Lenherr S . Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors. Cancer Res. 2004; 64(24):8811-5. DOI: 10.1158/0008-5472.CAN-04-3620. View

13.

Gold M, Lygren B, Dokurno P, Hoshi N, McConnachie G, Tasken K . Molecular basis of AKAP specificity for PKA regulatory subunits. Mol Cell. 2006; 24(3):383-95. DOI: 10.1016/j.molcel.2006.09.006. View

14.

Harada H, Becknell B, Wilm M, Mann M, Huang L, Taylor S . Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell. 1999; 3(4):413-22. DOI: 10.1016/s1097-2765(00)80469-4. View

15.

Samuel T, Okada K, Hyer M, Welsh K, Zapata J, Reed J . cIAP1 Localizes to the nuclear compartment and modulates the cell cycle. Cancer Res. 2005; 65(1):210-8. View

16.

Li X, Scuderi A, Letsou A, Virshup D . B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster. Mol Cell Biol. 2002; 22(11):3674-84. PMC: 133809. DOI: 10.1128/MCB.22.11.3674-3684.2002. View

17.

Hengartner M . The biochemistry of apoptosis. Nature. 2000; 407(6805):770-6. DOI: 10.1038/35037710. View

18.

Verdecia M, Huang H, Dutil E, Kaiser D, Hunter T, Noel J . Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. Nat Struct Biol. 2000; 7(7):602-8. DOI: 10.1038/76838. View

19.

Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I . HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 2003; 22(11):2729-40. PMC: 156760. DOI: 10.1093/emboj/cdg263. View

20.

Reed J . Apoptosis-targeted therapies for cancer. Cancer Cell. 2003; 3(1):17-22. DOI: 10.1016/s1535-6108(02)00241-6. View