Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Apoptosis and survival BAD phosphorylation

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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 [1].

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 [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 specificantiapoptotic 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 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[6]. 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 [7], [8].

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 [9], [10].

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 [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 atthreonine 201, thereby inhibiting BAD association with the antiapoptotic moleculeBCL-XL and BCL-2 [12].

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 [13], [14], [15], [16]. 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 [16].

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