Cells are usually surrounded by the extracellular matrix (ECM), and adhesion of the cells to the ECM is a key step in their migration through tissues. Integrins are important receptors for the ECM and form structures called focal adhesions (FAs). Formation and disassembly of FAs are regulated dynamically during cell migration. Adhesion to the ECM has been studied mainly using cells cultured on an ECM-coated substratum, where the rate of cell migration is determined by the turnover of FAs. However, the molecular events underlying the disassembly of FAs are less well understood. We have recently identified both a new regulator of this disassembly process and its interaction partners. Here, we summarize our understanding of FA disassembly by focusing on the proteins implicated in this process.
Early endosomes, also called sorting endosomes, are known to mature into late endosomes via the Rab5-mediated endolysosomal trafficking pathway. Thus, early endosome existence is thought to be maintained by the continual fusion of transport vesicles from the plasma membrane and the trans-Golgi network (TGN). Here we show instead that endocytosis is dispensable and post-Golgi vesicle transport is crucial for the formation of endosomes and the subsequent endolysosomal traffic regulated by yeast Rab5 Vps21p. Fittingly, all three proteins required for endosomal nucleotide exchange on Vps21p are first recruited to the TGN before transport to the endosome, namely the GEF Vps9p and the epsin-related adaptors Ent3/5p. The TGN recruitment of these components is distinctly controlled, with Vps9p appearing to require the Arf1p GTPase, and the Rab11s, Ypt31p/32p. These results provide a different view of endosome formation and identify the TGN as a critical location for regulating progress through the endolysosomal trafficking pathway.
Spot urine samples were collected from the inhabitants of two rural communities in northwestern Bangladesh. We compared arsenic levels in the urine samples ([As](u); n = 346) with those in water from tube wells ([As](tw); range < 1-535 microg/L; n = 86) on an individual basis. The small variation of [As](u) within subjects and highly positive correlation with [As](tw) indicate that [As](u) is a useful indicator of exposure. Analyses of [As](u) showed that creatinine correction was necessary, that [As](u) only reflected recent exposure, and that there were substantial interindividual differences for a given [As](tw) level. To evaluate the toxic effects of arsenic exposure, we constructed a system for rating skin manifestations, which revealed distinct sex-related differences. Comparison of males and females in the same households confirmed that skin manifestations were more severe in the males, and in the males of one community a dose-response relationship between [As](u) and the degree of skin manifestation was evident. The results of this study indicate that [As](u) in spot urine samples can be used as an exposure indicator for As. They suggest that there might be sex-related, and perhaps community-related, differences in the relationship between [As](u) and skin manifestations, although several confounding factors, including sunlight exposure and smoking habits, might contribute to the observed sex difference. The existence of such differences should be further confirmed and examined in other populations to identify the subpopulations sensitive to chronic arsenic toxicity.
The actin cytoskeleton plays important roles in the formation and internalization of endocytic vesicles. In yeast, endocytic vesicles move towards early endosomes along actin cables, however, the molecular machinery regulating interaction between endocytic vesicles and actin cables is poorly understood. The Eps15-like protein Pan1p plays a key role in actin-mediated endocytosis and is negatively regulated by Ark1 and Prk1 kinases. Here we show that pan1 mutated to prevent phosphorylation at all 18 threonines, pan1-18TA, displayed almost the same endocytic defect as ark1Δ prk1Δ cells, and contained abnormal actin concentrations including several endocytic compartments. Early endosomes were highly localized in the actin concentrations and displayed movement along actin cables. The dephosphorylated form of Pan1p also caused stable associations between endocytic vesicles and actin cables, and between endocytic vesicles and endosomes. Thus Pan1 phosphorylation is part of a novel mechanism that regulates endocytic compartment interactions with each other and with actin cables.DOI: http://dx.doi.org/10.7554/eLife.10276.001
The prevalence of arsenicosis was quite high and males were more vulnerable to arsenic contamination. Using skin manifestations, especially keratosis on the soles, as useful markers to detect and evaluate arsenicosis, it is clear that there is an urgent need to assess the exact prevalence and severity of arsenicosis in the population of Bangladesh in order to take measures to treat and control this problem.
HSC fate decisions are regulated by cellintrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP ؊/؊ mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH- 1 IntroductionThe adult hematopoietic system is maintained by a small number of HSCs that reside in the BM in a specialized microenvironment (the niche). 1,2 Here, HSCs undertake fate decisions including differentiation to progenitor cells and self-renewal, which ensures a lifelong supply of terminally differentiated blood cells. Intrinsic cellular programming and external stimuli such as adhesive interactions with the microenvironmental stroma and cytokine activities regulate HSC fate. However, it is unclear how niche factor production is controlled to adjust to external demand with a fine-tuned response.Hypoxia-inducible factors (HIFs) consist of an ␣ (HIF-␣) and a  (HIF-, or ARNT) subunit and activate the expression of genes encoding proteins that regulate cell metabolism, motility, angiogenesis, hematopoiesis, and other functions. HSCs maintain cell-cycle quiescence by regulating HIF-1␣ levels. 3,4 Mice with mutations in the heterodimeric transcription factor HIF develop extensive hematopoietic pathologies: embryos lacking Arnt have defects in primitive hematopoiesis. 5 Mice lacking endothelial PAS domain protein 1 (EPAS1, also known as HIF-2alpha/HRF/HLF/MOP3), a second HIF family member, exhibited pancytopenia, and it was shown that EPAS1 is necessary to maintain a functional microenvironment in the BM for effective hematopoiesis. 6 HIFs bind to canonical DNA sequences in the promoters or enhancers of target genes such as erythropoietin (Epo), vascular endothelial growth factor-A, SDF-1␣/CXCL12, angiopoietin-2, platelet-derived growth factor-B and Kit Ligand (KitL)/stem cell factor, which are involved in HSC maintenance within the BM niche. 7-10 The chemokine SDF-1␣/CXCL12 (SDF-1␣) is expressed by perivascular, endosteal, mesenchymal stem and progenitor cells as well as by osteoblasts. 11,12 SDF-1␣ deficiency leads to a reduction in HSCs and impaired B-cell development in mice. 13,14 IL-7 is another stromal cell-derived niche factor, which, in cooperation with CXCL12, functions at sequential stages of B-cell development. 15,16 IL-7 or IL-7R deficiency results in impaired B-cell development. 17,18 Proteases such as matrix metalloproteinase-9 (MMP-9) and the serine proteinase plasmin(ogen) regulate HSC fate through KitL release i...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.