Apoptosis and survival - BAD phosphorylation

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].

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].

References:

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