14-3-3 and Regulation of BAD Activity
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14-3-3 and Regulation of BAD Activity

The 14-3-3s are a family of regulatory proteins that is present in all eukaryotes and involved in protein interactions mediating signal transduction pathways. Numerous pathways and processes rely on the 14-3-3 interactions to regulate key metabolic points. The conservation of 14-3-3 structure among eukaryotes speaks to their essential nature, yet the divergence into so many isoforms in each of these species suggests an intricate network of roles for these proteins (Ref.1). The 14-3-3 proteins are molecular adaptors that integrate numerous signalling pathways, including the v-raf-leukaemia viral oncogene 1 (RAF1)/B cell leukaemia/lymphoma 2 (BCL-2)-associated agonist of cell death (BAD) pathway (Ref.2).

Phosphorylated BAD is sequestered in the cytoplasm by 14-3-3 scaffold, thereby preventing its mitochondrial translocation to induce apoptosis. 14-3-3 proteins are implicated in antagonizing apoptotic signals, mainly through the cytoplasmic sequestration of the proapoptotic proteins BAD and BAX. For example, a substantial proportion of BAD is bound to 14-3-3 proteins in the cytosol of healthy cells, regulated by phosphorylation through the PI3-kinase-Akt pathway. This association is disrupted in correlation with BAD translocation to mitochondria. Although phosphorylation prevents BAD from promoting cell death, its dephosphorylated form dissociates from 14-3-3 and redistributes to mitochondria, where cell death can be induced through binding of Bcl-2/BclXL (Ref.3). At least three more kinases are capable of phosphorylating BAD besides Akt1. They are PKA (Protein Kinase-A), PKC (Protein Kinase-C), and Raf1. However, of these, only PKA and Akt1 phosphorylate BAD at the S112 or S136 sites relevant to 14-3-3 interactions. Akt1 is broadly involved in cell survival and cell differentiation signaling. It is located in a pathway downstream of 14-3-3 (Phosphatidylinositol 3-Kinase) and thus is activated in response to a multitude of pro-survival signals, including IGF-I, IL-3 (Interleukin-3), and NGF (Nerve Growth Factor). Active Akt1 leads to the phosphorylation of S136 of BAD, association of 14-3-3 with BAD, and inhibition of BAD-induced cell death. Phosphorylation of BAD by Akt1 at S136 directly links a general survival-signaling pathway to a death promoter, one way in which survival factors can inhibit cell death (Ref.4). In addition, Akt1 promotes cell survival by phosphorylating other pro-apoptotic proteins such as FKHRL1 (Forkhead) and YAP (YES-Associated Protein), which then bind to 14-3-3 proteins and are inactivated by cytoplasmic sequestration. Binding to 14-3-3 also retains phosphorylated YAP in the cytoplasm, resulting in its displacement from the nucleus where it functions as a co-activator of p73-mediated apoptosis. When phosphorylated by Akt1, FKHRL1 becomes a 14-3-3 ligand and is no longer able to induce cell death. However when Akt1 becomes inactive and FKHRL1 become dephosphorylated it translocates to the nucleus and activates a variety of genes, including BIM (Ref.5). 14-3-3 proteins also interact directly with other BH3-domain proteins that are involved in the regulation of apoptosis, such as BAX (BCL2 Associated-X Protein). However, this association is not dependent on serine/threonine phosphorylation. On the other hand, interaction of 14-3-3 and TERT, the catalytic subunit of telomerase that prevents apoptosis, promotes its retention in the nucleus. Also, the death-promoting activity of ASK1 (Apoptosis Signal-regulating Kinase-1) and BAX is antagonized by its binding to 14-3-3 proteins after activation by TNF-Alpha (Tumor Necrosis Factor-Alpha). Modulation of activity of binding partners by NADE (p75 Neurotrophin Receptor (p75NTR)-Associated cell death Executor) and their function as A20 (Adapter molecules) are further mechanisms by which 14-3-3 proteins exert their function on Caspases like Caspase3 in the control of apoptosis (Ref.4).

The 14-3-3 proteins are a part of an emerging family of proteins and protein domains that bind and regulate key proteins involved in various cellular signaling circuits that are implicated in cancer development. They are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in regulation of cell cycle arrest in response to DNA damage, cell cycle timing, intracellular trafficking, regulation of ion channels, and intracellular signaling in response to stress, mating pheromone in yeast, photoreceptor development and learning in Drosophila, cellular response to stress and survival factors in mammals, and signaling pathways in various organisms (Ref.5).