We investigated the association between a U.S. National Institutes of Health (NIH) R01 applicant’s self-identified race or ethnicity and the probability of receiving an award by using data from the NIH IMPAC II grant database, the Thomson Reuters Web of Science, and other sources. Although proposals with strong priority scores were equally likely to be funded regardless of race, we find that Asians are 4 percentage points and black or African-American applicants are 13 percentage points less likely to receive NIH investigator-initiated research funding compared with whites. After controlling for the applicant’s educational background, country of origin, training, previous research awards, publication record, and employer characteristics, we find that black or African-American applicants remain 10 percentage points less likely than whites to be awarded NIH research funding. Our results suggest some leverage points for policy intervention.
Ubiquitin functions as a signal for sorting cargo at multiple steps of the endocytic pathway and controls the activity of trans-acting components of the endocytic machinery (reviewed in refs 1, and 2). By contrast to proteasome degradation, which generally requires a polyubiquitin chain that is at least four subunits long, internalization and sorting of endocytic cargo at the late endosome are mediated by mono-ubiquitination. Here, we demonstrate that ubiquitin-interacting motifs (UIMs) found in epsins and Vps27p (ref. 9) from Saccharomyces cerevisiae are required for ubiquitin binding and protein transport. Epsin UIMs are important for the internalization of receptors into vesicles at the plasma membrane. Vps27p UIMs are necessary to sort biosynthetic and endocytic cargo into vesicles that bud into the lumen of a late endosomal compartment, the multivesicular body. We propose that mono-ubiquitin regulates internalization and endosomal sorting by interacting with modular ubiquitin-binding domains in core components of the protein transport machinery. UIM domains are found in a broad spectrum of proteins, consistent with the idea that mono-ubiquitin can function as a regulatory signal to control diverse biological activities.
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Internalization of activated signaling receptors by endocytosis is one way cells downregulate extracellular signals. Like many signaling receptors, the yeast α-factor pheromone receptor is downregulated by hyperphosphorylation, ubiquitination, and subsequent internalization and degradation in the lysosome-like vacuole. In a screen to detect proteins involved in ubiquitin-dependent receptor internalization, we identified the sphingoid base–regulated serine–threonine kinase Ypk1. Ypk1 is a homologue of the mammalian serum– and glucocorticoid-induced kinase, SGK, which can substitute for Ypk1 function in yeast. The kinase activity of Ypk1 is required for receptor endocytosis because mutations in two residues important for its catalytic activity cause a severe defect in α-factor internalization. Ypk1 is required for both receptor-mediated and fluid-phase endocytosis, and is not necessary for receptor phosphorylation or ubiquitination. Ypk1 itself is phosphorylated by Pkh kinases, homologues of mammalian PDK1. The threonine in Ypk1 that is phosphorylated by Pkh1 is required for efficient endocytosis, and pkh mutant cells are defective in α-factor internalization and fluid-phase endocytosis. These observations demonstrate that Ypk1 acts downstream of the Pkh kinases to control endocytosis by phosphorylating components of the endocytic machinery.
This research expands efforts to understand differences in NIH funding associated with the self-identified race and ethnicity of applicants. We collected data from 2,397 NIH Biographical Sketches submitted between FY 2003 and 2006 as part of new NIH R01 Type 1 applications to obtain detailed information on the applicants’ training and scholarly activities, including publications. Using these data, we examined the association between an NIH R01 applicant’s race or ethnicity and the probability of receiving an R01 award. The applicant’s publication history as reported in the NIH biographical sketch and the associated bibliometrics narrowed the black/white funding gap for new and experienced investigators in explanatory models. We found that black applicants reported fewer papers on their Biosketches, had fewer citations, and those that were reported appeared in journals with lower impact factors. Incorporating these measures in our models explained a substantial portion of the black/white funding gap. Although these predictors influence the funding gap, they do not fully address race/ethnicity differences in receiving a priority score.
The formation of a primary endocytic vesicle is a dynamic process involving the transient organization of adaptor and scaffold proteins at the plasma membrane. Epsins and Eps15-like proteins are ubiquitin-binding proteins that act early in this process. Endocytosis is an essential process for regulating cell morphology and homeostasis. The formation of vesicles at the plasma membrane is highly regulated and is responsible for transporting transmembrane proteins and lipids into the cell. A dynamic network of endocytic proteins, including clathrin adaptors and clathrin, assembles at sites of vesicle formation where cargo is recruited into the nascent vesicle bud (1-3). Assembly of actin regulators and membrane-binding proteins at the endocytic network then facilitates vesicle invagination and scission (4-7). The tightly co-ordinated assembly and dissociation of endocytic network constituents require specific protein-protein and protein-lipid interactions (8,9).Endocytic adaptors and clathrin initiate the assembly of this network. Endocytic adaptors are multisubunit complexes or monomeric proteins that localize to the plasma membrane via lipid-binding domains and recruit clathrin to the membrane to form lattices enclosing nascent buds (3,10-12). These adaptors, including epsins, AP180 proteins and AP-2 complexes, recognize signals that target cargo for internalization. Adaptors also assemble later-acting endocytic proteins, known as scaffold proteins, which stabilize the adaptor-cargo-clathrin complex and regulate the assembly of actin required for endocytic vesicle maturation and internalization.Endocytic adaptors are conserved from yeast to mammals, and the clathrin-and actin-dependent endocytic pathway in yeast is an excellent model for clathrindependent internalization that occurs in mammalian cells. In Saccharomyces cerevisiae, the epsin and AP180 adaptors are functionally important and have overlapping roles (13,14). The epsins Ent1 and Ent2 are an essential gene pair with endocytic functions that are mostly redundant (15). They interact with phosphatidylinositol-(4,5)-bisphosphate at the plasma membrane via an epsin N-terminal homology (ENTH) domain and with ubiquitin via tandem ubiquitin-interacting motifs (UIMs). Both yeast epsins have two asparagine-proline-phenylalanine (NPF) motifs that are required for their proper localization during endocytosis and for interaction with the Eps15 homology (EH) domain-containing proteins, Ede1 and Pan1 (14,(16)(17)(18)(19). At the C-terminus, Ent1 and Ent2 bind to clathrin through a clathrin-binding motif (15,18). The AP180 proteins, Yap1801 and Yap1802, have an N-terminal AP180 N-terminal homology (ANTH) lipidbinding domain, multiple NPF motifs and a C-terminal clathrin-binding motif (16). Previous studies suggested that different protein-protein and protein-lipid interaction domains of the yeast monomeric clathrin adaptors have partially overlapping functions during receptor internalization. Specifically, Ent1 NPF motifs function co-operatively with lipid and clathri...
Efficient internalization of proteins from the cell surface is essential for regulating cell growth and differentiation. In a screen for yeast mutants defective in ligand-stimulated internalization of the alpha-factor receptor, we identified a mutant allele of TOR2, tor2G2128R. Tor proteins are known to function in translation initiation and nutrient sensing and are required for cell cycle progression through G1. Yeast Tor2 has an additional role in regulating the integrity of the cell wall by activating the Rho1 guanine nucleotide exchange factor Rom2. The endocytic defect in tor2G2128R cells is due to disruption of this Tor2 unique function. Other proteins important for cell integrity, Rom2 and the cell integrity sensor Wsc1, are also required for efficient endocytosis. A rho1 mutant specifically defective in activation of the glucan synthase Fks1/2 does not internalize alpha-factor efficiently, and fks1Delta cells exhibit a similar phenotype. Removal of the cell wall does not inhibit internalization, suggesting that the function of Rho1 and Fks1 in endocytosis is not through cell wall synthesis or structural integrity. These findings reveal a novel function for the Tor2-Rho1 pathway in controlling endocytosis in yeast, a function that is mediated in part through the plasma membrane protein Fks1.
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