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].
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 [18].