Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo. Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980. Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex vivo model of angiogenesis. Exposure of the aortic rings embedded in 3D fibrillar collagen to recombinant endorepellin for 2–4 h activated PERK and induced GADD45α vis à vis vehicle-treated counterparts. Similar effects were obtained with the established cellular stress inducer tunicamycin. Notably, chronic exposure of aortic rings to endorepellin for 7–9 days markedly suppressed vessel sprouting, an angiostatic effect that was rescued by blocking PERK kinase activity. Our findings unravel a mechanism by which an extracellular matrix protein evokes stress signaling in endothelial cells, which leads to angiostasis.

Noncoercive, pay-to-go, voluntary, assisted voluntary, and nonforced returns generally can offer paid travel and/or other financial incentive to encourage unauthorized immigrants to cooperate with immigration officials and leave host countries. A look at three key rationales for governments to choose pay-to-go and other returns.

Immigration is a prominent part of the United States’ DNA, despite concerns about immigrants’ ability to integrate. An examination of recent immigrant inflows shows newcomers to the United States are integrating well, based on language proficiency, socioeconomic attainment, political participation, residential locale, and social interaction indicators.

The U.S. refugee protection system, while generous in many respects, has become less robust over the last two decades. The unique and often diverse needs of emerging refugee populations have exposed severe limitations in the standard resettlement approach.This report examines U.S. legal and policy responses to those seeking protection and addresses the barriers, gaps, and opportunities that exist.

Illegal immigration is possible in large part because of illegal employment. This report shows the underlying drivers of illegal hiring vary based on the type of employer, the nature of the industry, state of the economy, and a country’s labor market institutions, employment legislation, immigration systems, and even culture.

Drawing on experiences from Asia, Europe, North America, and the Pacific region, this report presents eight strategies that represent best practices developed by immigrant-receiving countries to increase the economic contributions of immigration.

Two competing models for selecting economic-stream immigrants are now prevalent in advanced industrialized economies: points-based and employer-led selection. Increasingly, however, hybrid selection systems are being created, implementing best practices from each selection process.

The report examines U.S. immigration and international development policies, which have unique objectives and respond to distinct political and administrative constraints, and points out that international development has never been a U.S. immigration policy objective; nonetheless, it is an unintended consequence.

While aspects of the U.S. immigration system facilitate newcomers’ contributions to economic growth and competitiveness, others undermine them. Reforms are needed to enhance the job-creating power of U.S. employers and strengthen the system’s ability to select effectively from the large pool of foreign workers.

The exponential growth of international travel since the 1960s has left border management systems worldwide struggling to keep up and has exposed weaknesses in states’ abilities to effectively manage their borders, especially regarding terrorist attacks, human trafficking, and illegal migration.

This report explores the migration patterns and demographics of Black African immigrants in the United States, examining their admission channels, human-capital characteristics, and labor market performance. The authors also provide an analysis of these immigrants' integration prospects.

The EU-U.S. relationship is one of the most significant partnerships among wealthy nations. Interconnections between the two on migration issues make dialogue necessary and inevitable, as each relies on each other to attain a number of policy objectives, most clearly in the case of travel and border security.

This report describes the range of policies available to improve immigrants’ economic integration through language acquisition, especially those focused on getting immigrants into jobs or moving into higher-paying jobs. It assesses promising models and practices from Europe and North America.

Civil society provides a crucial link between governments and the communities they represent—infusing policy processes with grassroots knowledge to which governments may not otherwise have access. Looking at the European Union’s efforts to engage with civil society in its “neighborhood,” this report examines the benefits, challenges, and mechanisms to building dialogue and cooperation on migration and development.

Since 1970, the immigrant populations from Mexico and Central America living in the United States have increased significantly: rising by a factor of 20 even as the total U.S. immigrant population increased four-fold over the period. This demographic report examines the age, educational, and workforce characteristics of these immigrants.

Showcasing joint research by MPI and the European University Institute and funded by the European Commission, this event featured discussion on some of the most promising reform proposals on both sides of the Atlantic. Speakers discuss the project’s comparative research, which draws on MPI’s longstanding experience advising European and North American governments on immigration.

European dominance in U.S. immigration flows has decreased significantly since World War II, a result of economic, demographic, and policy trends on both sides of the Atlantic. Today, migration from European Union Member States to the United States, while small, is characterized by a substantial numbers of European scientists, professionals, and businesspeople.

The United States has historically offered unparalleled economic opportunity to successive generations of immigrants and their children, poised to play an increasing role in the U.S. economy. But the lasting impact of job loss and slower growth over the next decade will translate into fewer opportunities for workers—and immigrants may prove the most vulnerable.

This final report summarizes and reflects upon the key findings of the Improving EU and U.S. Immigration Systems: Learning from Experience comparative research project undertaken by MPI and the European University Institute through a grant from the European Commission.

Migration and development have emerged as a pressing policy priority on the global agenda. This report identifies critical lessons from the past decade of policy experimentation and offers recommendations for migration and development policy.