title: MADD is a downstream target of PTEN in triggering apoptosis.
abstract: Mitogen-activated kinase activating death domain containing protein (MADD) is abundantly expressed in cancer cells and necessary for maintaining cancer cell survival. However, this survival function of MADD is dependent upon its phosphorylation by protein kinase B (Akt). The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. The downstream targets of PTEN in triggering apoptosis have not yet been completely identified. Here, we report that MADD can act as a pro-apoptotic factor to initiate TRAIL-induced apoptosis when its phosphorylation is attenuated by PTEN. Our data show that tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induced a reduction in MADD phosphorylation with a concomitant up-regulation of PTEN. Knock down of PTEN using a specific siRNA prevented TRAIL-induced reduction in pMADD levels. Surprisingly, Akt non-phosphorylated MADD translocated from the plasma membrane to cytoplasm where it bound to 14-3-3 and displaced 14-3-3 associated Bax, which translocated to mitochondria resulting in cytochrome c release. Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612.
authors.forename: Shankar
authors.initials: S
authors.lastname: Jayarama
authors.forename: Liang-Cheng
authors.initials: LC
authors.lastname: Li
authors.forename: Lakshmy
authors.initials: L
authors.lastname: Ganesh
authors.forename: David
authors.initials: D
authors.lastname: Mardi
authors.forename: Prasad
authors.initials: P
authors.lastname: Kanteti
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Peifeng
authors.initials: P
authors.lastname: Li
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C482982:YWHAB protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: AKT; APOPTOSIS; MADD; PI3K; PTEN
references.citation: J Biol Chem. 2003 May 23;278(21):19426-35
references.pmid: 12642586
references.citation: J Clin Endocrinol Metab. 2009 Apr;94(4):1467-71
references.pmid: 19190106
references.citation: Cancer Res. 2003 Dec 15;63(24):8768-76
references.pmid: 14695193
references.citation: Cell. 2000 Jul 7;102(1):43-53
references.pmid: 10929712
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2586-91
references.pmid: 9482930
references.citation: Nat Rev Cancer. 2006 Mar;6(3):184-92
references.pmid: 16453012
references.citation: DNA Seq. 1996;6(5):263-73
references.pmid: 8988362
references.citation: J Biol Chem. 2010 Jul 16;285(29):22713-22
references.pmid: 20484047
references.citation: J Biol Chem. 2001 Dec 14;276(50):47202-11
references.pmid: 11577081
references.citation: EMBO J. 2007 Feb 7;26(3):902-13
references.pmid: 17235285
references.citation: EMBO J. 1999 Nov 1;18(21):6027-36
references.pmid: 10545114
references.citation: Cell. 1996 Nov 15;87(4):619-28
references.pmid: 8929531
references.citation: Oncogene. 2006 Oct 12;25(47):6252-61
references.pmid: 16682944
references.citation: Cell. 1997 Nov 14;91(4):479-89
references.pmid: 9390557
references.citation: J Biol Chem. 2005 Mar 18;280(11):10781-9
references.pmid: 15642728
references.citation: Cancer Res. 2008 Sep 15;68(18):7352-61
references.pmid: 18794122
references.citation: J Biol Chem. 2001 Nov 2;276(44):41318-24
references.pmid: 11533041
references.citation: Anticancer Drugs. 2007 Sep;18(8):861-74
references.pmid: 17667591
references.citation: Curr Opin Cell Biol. 2006 Dec;18(6):685-9
references.pmid: 17046225
references.citation: Cell. 2000 Jul 7;102(1):33-42
references.pmid: 10929711
references.citation: Oncogene. 2004 Feb 5;23(5):1076-87
references.pmid: 14716293
references.citation: Mol Cell. 2004 Dec 3;16(5):807-18
references.pmid: 15574335
references.citation: Cell. 1997 Oct 17;91(2):231-41
references.pmid: 9346240
references.citation: J Biol Chem. 2003 Jan 17;278(3):2058-65
references.pmid: 12426317
references.citation: PLoS One. 2013;8(2):e56817
references.pmid: 23457619
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11598-603
references.pmid: 11504915
references.citation: Cancer Res. 2004 Jun 15;64(12):4078-81
references.pmid: 15205314
references.citation: EMBO J. 2004 Apr 21;23(8):1889-99
references.pmid: 15071501
references.citation: Mol Cell Biol. 2008 Jan;28(2):564-74
references.pmid: 17998337
references.citation: Dev Cell. 2007 Apr;12(4):487-502
references.pmid: 17419990
references.citation: J Biol Chem. 2007 Oct 12;282(41):29967-76
references.pmid: 17698854
references.citation: Nature. 1999 Feb 4;397(6718):441-6
references.pmid: 9989411
references.citation: Thyroid. 2013 Jan;23(1):70-8
references.pmid: 22998497
references.citation: Am J Obstet Gynecol. 2011 Oct;205(4):362.e12-25
references.pmid: 21855847
references.citation: Biochem Biophys Res Commun. 2007 Jan 19;352(3):756-62
references.pmid: 17141194
references.citation: Cancer Gene Ther. 2005 Mar;12(3):228-37
references.pmid: 15550937
references.citation: J Biol Chem. 2004 May 14;279(20):21085-95
references.pmid: 14766748
references.citation: J Biol Chem. 1997 May 2;272(18):12069-75
references.pmid: 9115275
references.citation: Cell. 2007 Jun 29;129(7):1261-74
references.pmid: 17604717
references.citation: Oncogene. 2007 Feb 26;26(9):1338-45
references.pmid: 17322919
references.citation: Nat Cell Biol. 2001 Nov;3(11):973-82
references.pmid: 11715018
references.citation: J Biol Chem. 2007 Apr 20;282(16):11715-21
references.pmid: 17314102
references.citation: Oncogene. 2008 Sep 18;27(41):5527-41
references.pmid: 18794886