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
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 .
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 specific
antiapoptotic 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 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 . 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 , .
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 , .
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 .
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 at
threonine 201, thereby inhibiting BAD association with the antiapoptotic molecule
BCL-XL and BCL-2 .
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 , , , . 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 .
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 .
BAD, Bcl-2 and
Bcl-XL are involved in apoptosis - autophagy interplay.
Autophagy is negatively regulated by apoptosis-related proteins
Bcl-2 and Bcl-XL binding to
Beclin 1. BAD binding to Bcl-2
and Bcl-XL disrupts Bcl-2/
Bcl-XL - Beclin-1 interaction
leading to autophagy induction .
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