BAD is a Bcl-2 homology domain 3 (BH3)-only pro-apoptotic member of the Bcl-2 protein family that is regulated by phosphorylation in response to survival factors []. Binding of BAD to mitochondria is thought to be exclusively mediated by its BH3 domain. Membrane localisation of BAD mediates membrane translocation of Bcl-XL. The C-terminal part of BAD is sufficient for membrane binding. There are two segments with differing lipid-binding preferences, LBD1 and LBD2, that are responsible for this binding: (i) LBD1 located in the proximity of the BH3 domain (amino acids 122-131) and (ii) LBD2, the putative C-terminal α-helix-5 []. Phosphorylation-regulated 14-3-3 protein binding may expose the cholesterol-preferring LBD1 and bury the LBD2, thereby mediating translocation of BAD to raft-like micro-domains [].
This entry represents AF1q, encoded by the MLLT11 gene, which is a fusion partner of the MLL (mixed lineage leukemia) gene. The MLL-MLLT11 fusion is linked to the acute leukemias [].At the protein level, AF1q/MLLT11 is highly expressed in thymus and all leukemic cell lines, and is differentially expressed during neuronal differentiation [, ]. It interacts with the Notch signalling pathway to regulate the emergence of human prothymocytes []. It has also been shown that AF1q increases radiation-induced apoptosis through up-regulation of BAD (BCL-2 antagonist of cell death) in human squamous carcinoma via NF-kappaB [].
Cytokine-independent survival kinase (CISK also called SGK3) is a serine/threonine-protein kinase involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration []. It phosphorylates and inhibits the proapoptotic proteins, Bad and FKHRL1 []. CISK/SGK3 also regulates many transporters, ion channels, and receptors []. It plays a critical role in hair follicle morphogenesis and hair cycling []. N-terminal to a catalytic kinase domain, CISK contains a PX domain which binds highly phosphorylated PIs, directs membrane localization, and regulates the enzyme's activity [, ].This entry represents the PX domain of CISK.
14-3-3 tau/theta (tau in humans, theta in mice) isoform is encoded by the YWHAQ gene in humans and plays an important role in controlling apoptosis through interactions with ASK1, c-jun NH-terminal kinase, and p38 mitogen-activated protein kinase (MAPK). Its interaction with CDC25c regulates entry into the cell cycle and subsequent interaction with Bad prevents apoptosis. 14-3-3 theta protein expression is induced in patients with amyotrophic lateral sclerosis []. 14-3-3 tau is often overexpressed in breast cancer, which is associated with the downregulation of p21, a p53 target gene, and thus leads to tamoxifen resistance in MCF7 breast cancer cells and shorter patientsurvival. Therefore, 14-3-3 tau may be a potential therapeutic target in breast cancer []. Additionally, 14-3-3 theta mediates nucleocytoplasmic shuttling of the coronavirus nucleocapsid protein which causes severe acute respiratory syndrome []. 14-3-3 domain is an essential part of 14-3-3 proteins, a ubiquitous class of regulatory, phosphoserine/threonine-binding proteins found in all eukaryotic cells, including yeast, protozoa and mammalian cells [].
