Disease relevance of 14-3-3zeta

• We have observed that, in Drosophila cells, the 14-3-3zeta is up-regulated under heat stress conditions, a process mediated by a heat shock transcription factor [1].

Psychiatry related information on 14-3-3zeta

• Because strong mutations in this gene are lethal, we investigated the nature of the defects that precipitate the learning and memory deficit and the role of the two protein isoforms encoded by leonardo in these processes [2].
• The prevalence of functional 14-3-3 binding sites throughout the proteome, and especially among growth factor receptors and signaling molecules, reflects a global role for 14-3-3 in multiple cellular decision making [3].

High impact information on 14-3-3zeta

• Based on biochemical and functional data obtained with tissue culture cells and yeast, 14-3-3 proteins have been implicated in a number of different signal transduction processes, in particular in the signal-dependent activation of protein kinases [4].
• Requirement for Drosophila 14-3-3 zeta in Raf-dependent photoreceptor development [4].
• D14-3-3 zeta transcripts are strongly enriched in the developing central nervous system [4].
• We have solved the high-resolution X-ray structure of 14-3-3 bound to two different phosphoserine peptides, representing alternative substrate-binding motifs [5].
• Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding [5].

Biological context of 14-3-3zeta

• Site-directed mutations in its putative dimerization interface result in a dimerization-deficient form of D14-3-3zeta [6].
• As the biological action linked to heat stress, 14-3-3zeta interacted with apocytochrome c, a mitochondrial precursor protein of cytochrome c, in heat-treated cells, and the suppression of 14-3-3zeta expression by RNA interference resulted in the formation of significant amounts of aggregated apocytochrome c in the cytosol [1].
• Mutant alleles that reduce LEONARDO protein levels in the mushroom bodies significantly decrease the capacity for olfactory learning, but do not affect sensory modalities or brain neuroanatomy that are requisite for conditioning [7].
• The 14-3-3 proteins are highly conserved molecules that function as intracellular adaptors in a variety of biological processes, such as signal transduction, cell cycle control, and apoptosis [1].
• We find that antibody staining for 14-3-3 family members is cytoplasmic in interphase and perichromosomal in mitosis [8].

Anatomical context of 14-3-3zeta

• The Drosophila 14-3-3zeta gene leonardo is preferentially expressed in adult mushroom bodies, centers of insect learning and memory [2].
• These results suggest that Leonardo plays a role in the regulation of synaptic vesicle dynamics, a function which may underlie synaptic modulation properties enabling learning [9].
• Binding of 14-3-3 can lead to the activation of pump activity as in the case of the plasma membrane H+-ATPase or inhibition as in the case of the F-type ATP synthase complexes [10].

Associations of 14-3-3zeta with chemical compounds

• DNA sequencing showed that the cDNA-encoded protein is similar to a family of mammalian proteins, called 14-3-3, which activate tyrosine hydroxylase (TyrOHase) and tryptophan hydroxylase (TrpOHase), the two key enzymes regulating biosynthesis of biogenic monoamine neurotransmitters, such as dopamine and serotonin, in the brain [11].
• Most notably, 14-3-3 proteins bind to phosphoserine/phosphothreonine motifs in a sequence-specific manner [12].

Physical interactions of 14-3-3zeta

• Coimmunoprecipitation experiments from Drosophila heads and transfected cells confirm that 14-3-3 interacts with dSlo via Slob [13].
• The results provide evidence for a dSlo/Slob/14-3-3 regulatory protein complex [13].

Regulatory relationships of 14-3-3zeta

• We find that, in the absence of Tor, overexpression of leo is sufficient to activate tll expression [14].
• Slob binds to and modulates the Drosophila Slowpoke (dSlo) calcium-activated potassium channel and also recruits the ubiquitous signaling protein 14-3-3 to the channel regulatory complex [15].

Other interactions of 14-3-3zeta

• These data, taken together, suggest that monomeric D14-3-3zeta is capable of modulating dSlo channel activity in this regulatory complex [6].
• A yeast two-hybrid screen with Slob as bait identifies the zeta isoform of 14-3-3 as a Slob-binding protein [13].
• Drosophila 14-3-3 epsilon and 14-3-3 zeta proteins have been shown to function in RAS/MAP kinase pathways that influence the differentiation of the adult eye and the embryo [8].
• Revisiting three paradigmatic mutations altering olfactory learning and memory in Drosophila (dunce, leonardo, amnesiac) a link was established between each mutation and the operation of VDICs in Kenyon cells, the intrinsic neurons of the mushroom bodies (MBs) [16].
• These results suggest that the increased kinase activity of mutant D-Raf is caused by the selective loss of 14-3-3 binding to its amino terminus [17].

Analytical, diagnostic and therapeutic context of 14-3-3zeta

• Sequence analysis reveals that the cDNA-encoded protein shares 84% identity with the rat, human or sheep 14-3-3zeta isoform, and between 66% and 77% identity with bovine, human or rat beta, bovine gamma, human tau, Drosophila 14-3-3 and a previously isolated Xenopus member [18].
• Microinjection experiments showed a requirement for 14-3-3 function in mesodermal specification [19].

References