Pathway Map Details

Apoptosis and survival_BAD phosphorylation



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p90Rsk, MEK2(MAP2K2), IGF-1 receptor, 4.6.1.1, IRS-1, PP2A catalytic, PI3K reg class IA, MEK1(MAP2K1), p70 S6 kinase1, Adenylate cyclase type I, BAD, 14-3-3, p70 S6 kinase2, Shc, PtdIns(4,5)P2, Cytochrome c, Bcl-XL, Erk (MAPK1/3), Calcineurin A (catalytic), PP2C, PI3K cat class IA, PP1-cat alpha, GRB2, AKT(PKB), PDK (PDPK1), G-protein beta/gamma, PtdIns(3,4,5)P3, SOS, ATP cytosol, PKA-cat (cAMP-dependent), Bax, EGFR, PKA-reg (cAMP-dependent), BAD, c-Raf-1, Bcl-2, CDK1 (p34), 2.7.1.137, H-Ras, cAMP, JNK1(MAPK8), G-protein alpha-s

Description:

BAD phosphorylation

BAD is a member of the BCL-2 family. BCL-2 family members are regulators of the programmed cell death pathways.

BAD induces apoptosis by inhibiting antiapoptotic BCL-2-family members - BCL-x, Bcl-2, thereby allowing two other pro-apoptotic proteins, BAK and BAX, to aggregate and induce release of cytochrome c, followed by caspase activation and apoptosis [1].

Proapoptotic activity of BAD is regulated through its phosphorylation. Only the nonphosphorylated BAD heterodimerized with BCL-xl or Bcl-2. Phosphorylated BAD is sequestered in the cytosol by binding to 14-3-3 [2].

Five phosphorylation sites, all serines, had been identified on BAD: Ser112, Ser128, Ser136, Ser155 and Ser170, which are phosphorylated by a variety of kinases [3], [4].

It is generally believed that survival factors induce activation of specific antiapoptotic kinases, which modulate the activity of BAD [5].

In response to the activation of a insulin-like growth factor receptor ( IGF-1R ) and epidermal growth factor receptor ( EGFR ) occur activation phosphatidylinositol 3-kinase ( PI3K ) signaling cascade, which result to activation protein kinase B (PKB, also called Akt ) and 70-kDa ribosomal protein S6 kinases ( P70 S6 kinase 1 and P70 S6 kinase 1 2). AKT and P70 S6 kinases phosphorylate Ser-136 and inhibition of BAD [6]. Growth factors also activate RAS-ERK signaling cascade. The 90-kDa ribosomal S6 kinase ( p90RSK ), a downstream effector in the MAPK signaling cascade, inactivates the pro-apoptotic protein BAD by phosphorylation it at serine 112 [7], [8].

Adenylate cyclase, activated by GPCRs, is responsible for production of cAMP. cAMP-dependent protein kinase ( PKA ) catalyzed the phosphorylation of the BAD at Ser112 and Ser155 [9], [10].

Cyclin-dependent kinase 1( CDK1) catalyzes phosphorylation of BAD at a distinct site, serine 128. The phosphorylation of BAD serine 128 inhibits the interaction of growth factor-induced serine 136-phosphorylated BAD with 14-3-3 proteins and, thereby, induces BAD-mediated apoptosis [11].

It is not known what kinases phosphorylate BAD at Ser170 [4].

In response to interleukin-3 stimulus, mitogen-activated protein kinase 8 ( JNK1 ) can phosphorilate BAD. JNK1 phosphorylates BAD at threonine 201, thereby inhibiting BAD association with the antiapoptotic molecule BCL-XL and BCL-2 [12].

Under certain stress conditions, BAD is activated by dephosphorylation. Protein phosphotase 1 alpha ( PP1A ), protein phosphatases 2A ( PP2A ), 2B ( PP2B, calcineurin) and 2C ( PP2C )can participapate in thisprocess [13], [14], [15], [16]. These phosphotases act on Ser112 and Ser136 and, except PP2B, also can dephosphorylated Ser155. Only PP2C gives priority to P-Ser(155) compared to P-Ser(112) and P-Ser(136) on BAD [16].

Dephosphorylated BAD is released from 14-3-3 and becomes free to interact with anti-apoptotic Bcl-2 family members, thereby activating the apoptotic effector machinery [17].

References:

  1. Bergmann A
    Survival signaling goes BAD. Developmental cell 2002 Nov;3(5):607-8
  2. Rosenquist M
    14-3-3 proteins in apoptosis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]. 2003 Apr;36(4):403-8
  3. Burlacu A
    Regulation of apoptosis by Bcl-2 family proteins. Journal of cellular and molecular medicine 2003 Jul-Sep;7(3):249-57
  4. Klumpp S, Krieglstein J
    Serine/threonine protein phosphatases in apoptosis. Current opinion in pharmacology. 2002 Aug;2(4):458-62
  5. Jin Z, Gao F, Flagg T, Deng X
    Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. The Journal of biological chemistry 2004 May 28;279(22):23837-44
  6. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ
    p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proceedings of the National Academy of Sciences of the United States of America 2001 Aug 14;98(17):9666-70
  7. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME
    Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999 Nov 12;286(5443):1358-62
  8. Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo HM
    Mitogen-activated protein kinase pathway-dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapoptotic protein bad. Cancer research 2003 Dec 1;63(23):8330-7
  9. Lizcano JM, Morrice N, Cohen P
    Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. The Biochemical journal 2000 Jul 15;349(Pt 2):547-57
  10. Virdee K, Parone PA, Tolkovsky AM
    Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Current biology : CB 2000 Sep 21;10(18):1151-4
  11. Konishi Y, Lehtinen M, Donovan N, Bonni A
    Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Molecular cell 2002 May;9(5):1005-16
  12. Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN, Xiang J, Lin A
    JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Molecular cell 2004 Feb 13;13(3):329-40
  13. Ayllon V, Martinez-A C, Garcia A, Cayla X, Rebollo A
    Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. The EMBO journal 2000 May 15;19(10):2237-46
  14. Chiang CW, Harris G, Ellig C, Masters SC, Subramanian R, Shenolikar S, Wadzinski BE, Yang E
    Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 2001 Mar 1;97(5):1289-97
  15. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC
    Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999 Apr 9;284(5412):339-43
  16. Klumpp S, Selke D, Krieglstein J
    Protein phosphatase type 2C dephosphorylates BAD. Neurochemistry international 2003 Jun;42(7):555-60
  17. van Hemert MJ, Steensma HY, van Heusden GP
    14-3-3 proteins: key regulators of cell division, signalling and apoptosis. BioEssays : news and reviews in molecular, cellular and developmental biology 2001 Oct;23(10):936-46