Control of Cell Growth and Proliferation by the Tribbles Pseudokinase: Lessons from Drosophila.

The Tribbles (Trib) family of pseudokinase proteins regulate cell growth, proliferation, and differentiation during normal development and in response to environmental stress. Mutations in human Trib isoforms (Trib1, 2, and 3) have been associated with metabolic disease and linked to leukemia and the formation of solid tumors, including melanomas, hepatomas, and lung cancers. Drosophila Tribbles (Trbl) was the first identified member of this sub-family of pseudokinases and shares a conserved structure and similar functions to bind and direct the degradation of key mediators of cell growth and proliferation.

FijiWingsPolarity: An open source toolkit for semi-automated detection of cell polarity.

Epithelial cells are defined by apical-basal and planar cell polarity (PCP) signaling, the latter of which establishes an orthogonal plane of polarity in the epithelial sheet. PCP signaling is required for normal cell migration, differentiation, stem cell generation and tissue repair, and defects in PCP have been associated with developmental abnormalities, neuropathologies and cancers. While the molecular mechanism of PCP is incompletely understood, the deepest insights have come from Drosophila, where PCP is manifest in hairs and bristles across the adult cuticle and organization of the ommatidia in the eye.

A model of insulin resistance associated with the human TRIB3 Q/R polymorphism.

Members of the Tribbles family of proteins are conserved pseudokinases with diverse roles in cell growth and proliferation. Both Tribbles (Trbl) and vertebrate Trib3 proteins bind to the kinase Akt (Akt1) to block its phosphorylation activation and reduce downstream insulin-stimulated anabolism. A single nucleotide polymorphism (SNP) variant in human TRIB3, which results in a glutamine (Q) to arginine (R) missense mutation in a conserved motif at position 84, confers stronger Akt binding, resulting in reduced Akt phosphorylation, and is associated with a predisposition to Type 2 diabetes, cardiovascular disease, diabetic nephropathy, chronic kidney disease and leukemogenesis.

Conservation of gene and tissue networks regulating insulin signalling in flies and vertebrates.

Fruit flies have emerged as a powerful tool to investigate metabolism. Not only are gene structures and gene networks that control metabolism conserved through evolution, but the interactions among organs to store and process metabolites have strong similarities between flies and humans. Accordingly, the Drosophila system has the potential to address human disorders associated with metabolic dysfunction including obesity, type 2 diabetes and lipotoxicity.

Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase.

Drosophila Tribbles (Trbl) is the founding member of the Trib family of kinase-like docking proteins that modulate cell signaling during proliferation, migration and growth. In a wing misexpression screen for Trbl interacting proteins, we identified the Ser/Thr protein kinase Akt1. Given the central role of Akt1 in insulin signaling, we tested the function of Trbl in larval fat body, a tissue where rapid increases in size are exquisitely sensitive to insulin/insulin-like growth factor levels.

FijiWings: an open source toolkit for semiautomated morphometric analysis of insect wings.

Development requires coordination between cell proliferation and cell growth to pattern the proper size of tissues, organs, and whole organisms. The Drosophila wing has landmark features, such as the location of veins patterned by cell groups and trichome structures produced by individual cells, that are useful to examine the genetic contributions to both tissue and cell size. Wing size and trichome density have been measured manually, which is tedious and error prone, and although image processing and pattern-recognition software can quantify features in micrographs, this approach has not been applied to insect wings.

The kinase domain of Drosophila Tribbles is required for turnover of fly C/EBP during cell migration.

Drosophila Tribbles (Trbl) encodes the founding member of the Trib family of kinase-like proteins that regulate cell migration, proliferation, growth and homeostasis. Trbl was identified in a misexpression screen in the ovary as an antagonist of border cell migration and acts in part by directing turnover of the C/EBP protein encoded by the gene slow border cells (slbo). The ability of mammalian Trib isoforms to promote C/EBP turnover during tissue differentiation indicates that this function is highly conserved.

Developmental roles of tribbles protein family members.

The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested.

A dominant negative allele of the Drosophila leucine zipper protein Bunched blocks bunched function during tissue patterning.

The bunched (bun) gene encodes the Drosophila member of the TSC-22/GILZ family of leucine zipper transcriptional regulators. The bun locus encodes multiple BUN protein isoforms and has diverse roles during patterning of the eye, wing margin, dorsal notum and eggshell. Here we report the construction and activity of a dominant negative allele (BunDN) of the BUN-B isoform.

The Drosophila STAT protein, stat92E, regulates follicle cell differentiation during oogenesis.

Signal transducer and activator of transcription (STAT) proteins are transcription factors that play a critical role in the response of a variety of eukaryotic cells to cytokine and growth factor signaling. In Drosophila, the STAT homolog encoded by the stat92E gene is required for the normal development of multiple tissues, including embryonic segmentation, imaginal discs, blood cells, male germ cells, and sex determination. We used multiple approaches to study the role of stat92E in oogenesis.