A5034584787- Cell Adhesion Molecules Research
- Renal and related cancers
- Chronic Kidney Disease and Diabetes
- Renal Diseases and Glomerulopathies
- Renal cell carcinoma treatment
- Cellular Mechanics and Interactions
- Eicosanoids and Hypertension Pharmacology
- Protease and Inhibitor Mechanisms
- Peroxisome Proliferator-Activated Receptors
- TGF-β signaling in diseases
- Peptidase Inhibition and Analysis
- Adipose Tissue and Metabolism
- Cancer Research and Treatments
- Angiogenesis and VEGF in Cancer
- Ferroptosis and cancer prognosis
- Neonatal Respiratory Health Research
- S100 Proteins and Annexins
- Cancer Genomics and Diagnostics
- Genetic and Kidney Cyst Diseases
- Receptor Mechanisms and Signaling
- Inflammatory mediators and NSAID effects
- Tissue Engineering and Regenerative Medicine
- Platelet Disorders and Treatments
- Caveolin-1 and cellular processes
- Immune Response and Inflammation
Vanderbilt University Medical Center
2016-2025
VA Tennessee Valley Healthcare System
2012-2024
Vanderbilt-Ingram Cancer Center
2001-2024
Vanderbilt University
2014-2024
Hypertension Institute
2018-2024
University of Fort Lauderdale
2023
Florida State University
2022
Veterans Health Administration
2007-2022
Nashville Oncology Associates
2019
Tennessee Oncology
2007-2018
The β subunit cytoplasmic domains of integrin adhesion receptors are necessary for the connection these to actin cytoskeleton. protein, talin, binds tails and filaments, hence forming an integrin-cytoskeletal linkage. We used recombinant structural mimics β<sub>1</sub>A, β<sub>1</sub>D β<sub>3</sub>integrin characterize integrin-binding sites within talin. Here we report that site is localized N-terminal talin head domain. binding domain specific in it abrogated by a single point mutation...
Control of integrin activation is required for cell adhesion and ligand-induced signaling. Here we report that loss the focal protein Kindlin-2 in mice results peri-implantation lethality caused by severe detachment endoderm epiblast from basement membrane. We found Kindlin-2-deficient cells were unable to activate their integrins talin-induced activation. Furthermore, demonstrate outside-in signaling enable firm spreading. Our findings provide evidence a novel essential element bidirectional
Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects oxidative metabolism. Due to local hypoxia and hypertonicity, renal medulla subject extreme stress. Here, we set out investigate role Sirt1 in kidney. Our initial analysis indicated it was abundantly expressed mouse medullary interstitial cells vivo. Knocking down expression primary substantially reduced cellular resistance stress, while pharmacologic activation using either resveratrol or SRT2183...
Integrins require an activation step prior to ligand binding and signaling. How talin kindlin contribute these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either or failed activate β1 integrins, adhere fibronectin (FN) maintain their integrins a high affinity conformation induced by Mn(2+). Despite compromised integrin adhesion, Mn(2+) enabled talin- but not kindlin-deficient initiate spreading on FN. This isotropic was the ability of...
Abstract The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading migration. Here, we demonstrate how the actin-binding proteins talin vinculin cooperate to provide this link. By expressing structure-based mutants in null cells, show that while C-terminal site (ABS3) required adhesion complex assembly, central ABS2 focal (FA) maturation. Thus, although support spreading, cells lack FAs, fail polarize exert reduced force on surrounding...
Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary cells. TGF-β-meditated EMT involves the stimulation of a number signaling pathways by sequential binding type II and I serine/threonine kinase receptors, respectively. Integrins comprise family heterodimeric extracellular matrix receptors that mediate cell adhesion intracellular signaling, hence making them crucial for progression. In light substantial evidence indicating TGF-β...
The glomerulus contains unique cellular and extracellular matrix (ECM) components, which are required for intact barrier function. Studies of the components have helped to build understanding glomerular disease; however, full composition regulation ECM remains poorly understood. We used mass spectrometry-based proteomics enriched extracts a global analysis human in vivo identified tissue-specific proteome 144 structural regulatory proteins. This catalog includes all previously plus many new...
The cytochrome P450 arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs) are powerful, nonregioselective, stimulators of cell proliferation. In this study we compared ability four EETs (5,6-, 8,9-, 11,12-, and 14,15-EETs) to regulate endothelial proliferation in vitro angiogenesis vivo determined molecular mechanism by which control these events. Inhibition blocked serum-induced proliferation, exogenously added rescued from inhibition. Studies with selective ERK,...
Podocytes are specialized actin-rich epithelial cells that line the kidney glomerular filtration barrier. The interface between podocyte and basement membrane requires integrins, defects in either α3 or β1 integrin, α3β1 ligand laminin result nephrotic syndrome murine models. large cytoskeletal protein talin1 is not only pivotal for integrin activation, but also directly links integrins to actin cytoskeleton. Here, we found mice lacking specifically podocytes display severe proteinuria, foot...
Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell by directly binding recruiting paxillin nascent adhesions. Here, we report that has dual during initial spreading: it binds via pleckstrin homology F0 domains activate Rac1, associates with Arp2/3 complex induce Rac1-mediated protrusions. Consistently, abrogation impairs lamellipodia...
The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It integral to capillary wall therefore, functionally linked filtration. Although composition GBM has been investigated with global candidate-based approaches, relative contributions cell types production ECM are not well understood. To characterize specific cellular GBM, we used mass spectrometry–based...
Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in pathophysiology of hypertension, leading cause cardiovascular, cerebral, renal morbidity mortality. We show here that disruption murine P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes type hypertension is, like most human dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when normal or high-salt diets. Hypertensive...
Abstract It has been proposed that cross talk between integrin and growth factor receptor signaling such as ErbB2 (HER2) is required for activation of downstream effectors ErbB2-mediated mammary tumorigenesis. Here we show transforming β (TGF-β) induced focal adhesion kinase (FAK)–dependent clustering HER2 integrins α6, β1, β4 in HER2-overexpressing epithelial cells without altering the total surface levels receptors. This effect was mediated by ligand-induced epidermal (EGFR) subsequent...
Prostaglandin E2 (PGE2), a major product of cyclooxygenase, exerts its functions by binding to four G protein-coupled receptors (EP1–4) and has been implicated in modulating angiogenesis. The present study examined the role EP4 receptor regulating endothelial cell proliferation, migration, tubulogenesis. Primary pulmonary microvascular cells were isolated from EP4flox/flox mice rendered null for with adenoCre virus. Whereas treatment PGE2 or selective agonists PGE1-OH ONO-AE1–329 induced...
Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation collagen synthesis. Mesangial cells, found in the glomerulus kidney, are able to produce large amounts ROS via NADPH oxidase. We previously demonstrated that integrin α1-null mice develop worse fibrosis than wild-type following glomerular injury this is due, part, excessive production by mesangial cells. In present studies, we describe mechanism whereby cells ROS. Integrin have...
ABSTRACT Reovirus cell entry is mediated by attachment to surface carbohydrate and junctional adhesion molecule A (JAM-A) internalization β1 integrin. The integrin cytoplasmic tail contains two NPXY motifs, which function in recruitment of adaptor proteins clathrin for endocytosis serve as sorting signals internalized cargo. As reovirus infection requires disassembly the endocytic compartment, we investigated role motifs internalization. In comparison wild-type cells (β1+/+ cells),...
The filtration unit of the kidney is glomerulus, a capillary network supported by mesangial cells and extracellular matrix (ECM). Glomerular function compromised in diabetic nephropathy (DN) uncontrolled buildup ECM, especially type IV collagen, which progressively occludes capillaries. Increased levels ECM protein fibronectin (FN) are also present; however, its role DN unknown. Mesangial cultured under high glucose conditions provide model system for studying effect elevated on deposition...