Ligand Independence of the T618I Mutation in the Colony-stimulating Factor 3 Receptor (CSF3R) Protein Results from Loss of O-Linked Glycosylation and Increased Receptor Dimerization

Mutations in the CSF3 granulocyte colony-stimulating factor receptor CSF3R have recently been found in a large percentage of patients with chronic neutrophilic leukemia and, more rarely, in other types of leukemia. These CSF3R mutations fall into two distinct categories: membrane-proximal mutations and truncation mutations. Although both classes of mutation have exhibited the capacity for cellular transformation, several aspects of this transformation, including the kinetics, the requirement for ligand, and the dysregulation of downstream signaling pathways, have all been shown to be discrepant between the mutation types, suggesting distinct mechanisms of activation. CSF3R truncation mutations induce overexpression and ligand hypersensitivity of the receptor, likely because of the removal of motifs necessary for endocytosis and degradation. In contrast, little is known about the mechanism of activation of membrane-proximal mutations, which are much more commonly observed in chronic neutrophilic leukemia. In contrast with CSF3R truncation mutations, membrane-proximal mutations do not exhibit overexpression and are capable of signaling in the absence of ligand. We show that the Thr-615 and Thr-618 sites of membrane-proximal mutations are part of an O-linked glycosylation cluster. Mutation at these sites prevents O-glycosylation of CSF3R and increases receptor dimerization. This increased dimerization explains the ligand-independent activation of CSF3R membrane-proximal mutations. Cytokine receptor activation through loss of O-glycosylation represents a novel avenue of aberrant signaling. Finally, the combination of the CSF3R membrane proximal and truncation mutations, as has been reported in some patients, leads to enhanced cellular transformation when compared with either mutation alone, underscoring their distinct mechanisms of action.     

Arts students in debt: Concerns,consequences, and interventions

While there are many educational and experiential benefits to attending professional higher arts education programs, students who incur excessive student loan debt during their studies may experience unanticipated or poor professional outcomes either over the course of their artistic careers, shortly after the expiration of a loan grace period, or after they can no longer defer payments. To date, little to no research exists on the effects of an excessive student loan debt burden on professional arts careers. To address this gap in the higher arts education literature, and in an effort to facilitate scholarly discussion on the topic, this article identifies concerns, consequences, and potential interventions.     

Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors

Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature-sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At ≤20°C, glp-1(ar202) is wild-type, whereas at 25°C it forms a germline stem cell⁄progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2⁄M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models.     

Yeast as a model system for understanding the control of DNA replication in eukaryotes

In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the initiation of DNA replication is controlled at a point called START. At this point, the cellular environment is assessed; only if conditions are appropriate do cells traverse START, thus becoming committed to initiate DNA replication and complete the remainder of the cell cycle. The cdc2⁺ / CDC28⁺ gene, encoding the protein kinase p34, is a key element in this complex control. The identification of structural and functional homologues of p34 suggests that it has a role in the control of DNA replication in all eukaryotes. The WHI1⁺, CLN1⁺ and CLN2⁺ gene products, identified in S. cerevisiae, are positive regulators that function at START and may interact with p34. Determining how passing the START control point leads to the initiation of DNA replication is a major outstanding challenge in cell cycle studies.     

Organization of Enzyme Concentration across the Metabolic Network in Cancer Cells

Rapid advances in mass spectrometry have allowed for estimates of absolute concentrations across entire proteomes, permitting the interrogation of many important biological questions. Here, we focus on a quantitative aspect of human cancer cell metabolism that has been limited by a paucity of available data on the abundance of metabolic enzymes. We integrate data from recent measurements of absolute protein concentration to analyze the statistics of protein abundance across the human metabolic network. At a global level, we find that the enzymes in glycolysis comprise approximately half of the total amount of metabolic proteins and can constitute up to 10% of the entire proteome. We then use this analysis to investigate several outstanding problems in cancer metabolism, including the diversion of glycolytic flux for biosynthesis, the relative contribution of nitrogen assimilating pathways, and the origin of cellular redox potential. We find many consistencies with current models, identify several inconsistencies, and find generalities that extend beyond current understanding. Together our results demonstrate that a relatively simple analysis of the abundance of metabolic enzymes was able to reveal many insights into the organization of the human cancer cell metabolic network.     

Global domination by crazy ants: phylogenomics reveals biogeographical history and invasive species relationships in the genus Nylanderia (Hymenoptera: Formicidae)

Nylanderia (Emery) is one of the world's most diverse ant genera, with 123 described species worldwide and hundreds more undescribed. Fifteen globetrotting or invasive species have widespread distributions and are often encountered outside their native ranges. A molecular approach to understanding the evolutionary history and to revision of Nylanderia taxonomy is needed because historical efforts based on morphology have proven insufficient to define major lineages and delimit species boundaries, especially where adventive species are concerned. To address these problems, we generated the first genus-wide genomic dataset of Nylanderia using ultraconserved elements (UCEs) to resolve the phylogeny of major lineages, determine the age and origin of the genus, and describe global biogeographical patterns. Sampling from seven biogeographical regions revealed a Southeast Asian origin of Nylanderia in the mid-Eocene and four distinct biogeographical clades in the Nearctic, the Neotropics, the Afrotropics/Malagasy region, and Australasia. The Nearctic and Neotropical clades are distantly related, indicating two separate dispersal events to the Americas between the late Oligocene and early Miocene. We also addressed the problem of misidentification that has characterized species-level taxonomy in Nylanderia as a result of limited morphological variation in the worker caste by evaluating the integrity of species boundaries in six of the most widespread Nylanderia species. We sampled across ranges of species in the N. bourbonica complex (N. bourbonica (Forel) + N. vaga (Forel)), the N. fulva complex (N. fulva (Mayr) + N. pubens (Forel)), and the N. guatemalensis complex (N. guatemalensis (Forel) + N. steinheili (Forel)) to clarify their phylogenetic placement. Deep splits within these complexes suggest that some species names – specifically N. bourbonica and N. guatemalensis – each are applied to multiple cryptic species. In exhaustively sampling Nylanderia diversity in the West Indies, a ‘hot spot’ for invasive taxa, we found five adventive species among 22 in the region; many remain morphologically indistinguishable from one another, despite being distantly related. We stress that overcoming the taxonomic impediment through the use of molecular phylogeny and revisionary study is essential for conservation and invasive species management.