Apoptosis and survival BAD phosphorylation
BAD phosphorylation BAD is a member of the BCL-2 family. BCL-2 family members are regulators of theprogrammed 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 bycaspase activation and apoptosis . Proapoptotic activity of BAD is regulated through its phosphorylation. Only thenonphosphorylated BAD heterodimerized with BCL-xl or Bcl-2.Phosphorylated BAD is sequestered in the cytosol by binding to 14-3-3 . Five phosphorylation sites, all serines, had been identified on BAD: Ser112, Ser128,Ser136, Ser155 and Ser170, which are phosphorylated by a variety of kinases , . It is generally believed that survival factors induce activation of specificantiapoptotic kinases, which modulate the activity of BAD . In response to the activation of a insulin-like growth factor receptor ( IGF-1R) and epidermal growth factor receptor ( EGFR ) occur activationphosphatidylinositol 3-kinase ( PI3K ) signaling cascade, which result toactivation protein kinase B (PKB, also called Akt ) and 70-kDa ribosomal proteinS6 kinases ( P70 S6 kinase 1 and P70 S6 kinase 1 2).AKT and P70 S6 kinases phosphorylate Ser-136 and inhibition of BAD. Growth factors also activate RAS-ERK signaling cascade. The 90-kDaribosomal S6 kinase ( p90RSK ), a downstream effector in the MAPK signalingcascade, inactivates the pro-apoptotic protein BAD by phosphorylation it at serine112 , . Adenylate cyclase, activated by GPCRs, is responsible for production of cAMP.cAMP-dependent protein kinase ( PKA ) catalyzed the phosphorylation of theBAD at Ser112 and Ser155 , . Cyclin-dependent kinase 1( CDK1) catalyzes phosphorylation of BAD at adistinct site, serine 128. The phosphorylation of BAD serine 128 inhibits theinteraction of growth factor-induced serine 136-phosphorylated BAD with 14-3-3proteins and, thereby, induces BAD-mediated apoptosis . It is not known what kinases phosphorylate BAD at Ser170 . In response to interleukin-3 stimulus, mitogen-activated protein kinase 8 (JNK1 ) can phosphorilate BAD. JNK1 phosphorylates BAD atthreonine 201, thereby inhibiting BAD association with the antiapoptotic moleculeBCL-XL and BCL-2 . Under certain stress conditions, BAD is activated by dephosphorylation. Proteinphosphotase 1 alpha ( PP1A ), protein phosphatases 2A ( PP2A ), 2B (PP2B, calcineurin) and 2C ( PP2C )can participapate in thisprocess , , , . These phosphotases acton Ser112 and Ser136 and, except PP2B, also can dephosphorylated Ser155. OnlyPP2C gives priority to P-Ser(155) compared to P-Ser(112) and P-Ser(136) onBAD . Dephosphorylated BAD is released from 14-3-3 and becomes free tointeract with anti-apoptotic Bcl-2 family members, thereby activating the apoptoticeffector machinery .