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Rab4 knockdown

Ihsan Chrifi, Laura Louzao-Martinez, Maarten M Brandt, Christian G M van Dijk, Petra E Bürgisser, Changbin Zhu, Johan M Kros, Marianne C Verhaar, Dirk J Duncker, Caroline Cheng
Vascular endothelial (VE) cadherin is a key component of endothelial adherens junctions (AJs) and plays an important role in maintaining vascular integrity. Endocytosis of VE-cadherin regulates junctional strength and a decrease of surface VE-cadherin reduces vascular stability. However, disruption of AJs is also a requirement for vascular sprouting. Identifying novel regulators of endothelial endocytosis could enhance our understanding of angiogenesis. Here, we evaluated the angiogenic potential of (CKLF-like MARVEL transmembrane domain 4) CMTM4 and assessed in which molecular pathway CMTM4 is involved during angiogenesis...
August 10, 2018: Angiogenesis
John P Bannister, Simon Bulley, M Dennis Leo, Michael W Kidd, Jonathan H Jaggar
Plasma membrane-localized CaV1.2 channels are the primary calcium (Ca(2+)) influx pathway in arterial smooth muscle cells (myocytes). CaV1.2 channels regulate several cellular functions, including contractility and gene expression, but the trafficking pathways that control the surface expression of these proteins are unclear. Similarly, expression and physiological functions of small Rab GTPases, proteins that control vesicular trafficking in arterial myocytes, are poorly understood. Here, we investigated Rab proteins that control functional surface abundance of CaV1...
June 1, 2016: American Journal of Physiology. Cell Physiology
Maria J Gomez-Lamarca, Laura A Snowdon, Ekatarina Seib, Thomas Klein, Sarah J Bray
Notch signaling is a major regulator of cell fate, proliferation, and differentiation. Like other signaling pathways, its activity is strongly influenced by intracellular trafficking. Besides contributing to signal activation and down-regulation, differential fluxes between trafficking routes can cause aberrant Notch pathway activation. Investigating the function of the retromer-associated DNAJ protein Rme-8 in vivo, we demonstrate a critical role in regulating Notch receptor recycling. In the absence of Rme-8, Notch accumulated in enlarged tubulated Rab4-positive endosomes, and as a consequence, signaling was compromised...
July 20, 2015: Journal of Cell Biology
Jing Qian, Chun Wu, Xiaopan Chen, Xiangmei Li, Guoyuan Ying, Lili Jin, Qiang Ma, Guo Li, Ying Shi, Guozheng Zhang, Naiming Zhou
G protein-coupled receptor 40 (GPR40) is believed to be an attractive target to enhance insulin secretion in patients with type 2 diabetes. GPR40 has been found to couple to Gq protein, leading to the activation of phospholipase C and subsequent increases in the intracellular Ca(2+) level. However, the underlying mechanisms that regulate the internalization and desensitization of GPR40 remain to be elucidated. In the present study, a construct of GPR40 fused with enhanced green fluorescent protein (EGFP) at its C-terminus was constructed for direct imaging of the localization and internalization of GPR40 by confocal microscopy...
November 2014: Cellular Signalling
Ryan S D'Souza, Rachel Semus, Emily A Billings, Corey B Meyer, Kathryn Conger, James E Casanova
BACKGROUND: Early, sorting endosomes are a major crossroad of membrane traffic, at the intersection of the endocytic and exocytic pathways. The sorting of endosomal cargo for delivery to different subcellular destinations is mediated by a number of distinct coat protein complexes, including adaptor protein 1 (AP-1), AP-3, and Golgi-localized, gamma adaptin ear-containing, Arf-binding (GGAs) protein. Ultrastructural studies suggest that these coats assemble onto tubular subdomains of the endosomal membrane, but the mechanisms of coat recruitment and assembly at this site remain poorly understood...
June 2, 2014: Current Biology: CB
Aparna Mukhopadhyay, Jose A Quiroz, Allan W Wolkoff
We previously reported that Rab1a is associated with asialoorosomucoid (ASOR)-containing early endocytic vesicles, where it is required for their microtubule-based motility. In Rab1a knockdown (KD) cell lines, ASOR failed to segregate from its receptor and, consequently, did not reach lysosomes for degradation, indicating a defect in early endosome sorting. Although Rab1 is required for Golgi/endoplasmic reticulum trafficking, this process was unaffected, likely due to retained expression of Rab1b in these cells...
March 1, 2014: American Journal of Physiology. Gastrointestinal and Liver Physiology
Christopher J Smith, C Jane McGlade
The ubiquitin proteasome system is central to the regulation of a number of intracellular sorting pathways in mammalian cells including quality control at the endoplasmic reticulum and the internalization and endosomal sorting of cell surface receptors. Here we describe that RNF126, an E3 ubiquitin ligase, is involved in the sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). In cells transiently depleted of RNF126, the CI-MPR is dispersed into Rab4 positive endosomes and the efficiency of retrograde sorting is delayed...
January 15, 2014: Experimental Cell Research
René Keil, Mechthild Hatzfeld
p0071 is an intercellular junction protein of the p120 catenin family. We have identified Rab11a as a novel interaction partner of p0071. p0071 interacted preferentially with active Rab11a. Knockdown experiments revealed an interdependent regulation of both proteins. On the one hand, p0071 depletion induced a perinuclear accumulation of Rab11, suggesting a role of p0071 in the anterograde transport of Rab11 from the pericentrosomal region to the plasma membrane but not in retrograde transport. p0071 as well as Rab11 depletion increased transferrin receptor recycling indicating that p0071-induced Rab11 mislocalization interfered with Rab11 function and shifted recycling from the slow Rab11-dependent pathway to the fast Rab4-dependent pathway...
January 1, 2014: Journal of Cell Science
Jia Cheng, Wenhua Liu, Lara J Duffney, Zhen Yan
The group II metabotropic glutamate receptors (group II mGluRs) have emerged as the new drug targets for the treatment of mental disorders like schizophrenia. To understand the potential mechanisms underlying the antipsychotic effects of group II mGluRs, we examined their impact on NMDA receptors (NMDARs), since NMDAR hypofunction has been implicated in schizophrenia. The activation of group II mGluRs caused a significant enhancement of NMDAR currents in cortical pyramidal neurons, which was associated with increased NMDAR surface expression and synaptic localization...
August 15, 2013: Journal of Physiology
Yumika Kondo, Ayako Hanai, Waka Nakai, Yohei Katoh, Kazuhisa Nakayama, Hye-Won Shin
Small GTPases ARF1 and ARF3 localize mainly to the Golgi apparatus, where they trigger formation of coated carrier vesicles. We previously showed that BIG2, a guanine nucleotide exchange factor specific for ARF1 and ARF3, localizes not only to the trans-Golgi network (TGN) but also to recycling endosomes, where it is involved in regulating the integrity of recycling endosomes. However, it is not yet clear whether ARF1 and ARF3 act downstream of BIG2 to ensure endosome integrity. In this study, we show that EGFP-tagged ARF1 and ARF3 localize to endosomal compartments containing endocytosed transferrin...
2012: Cell Structure and Function
Li Hou, Mei-Juan Cai, Wen Liu, Qian Song, Xiao-Fan Zhao
The insulin and 20-hydroxyecdysone (20E) pathways coordinately regulate insect growth and metamorphosis. However, the molecular mechanism of the interaction of these two pathways in regulating insect development is not well understood. In the present study, we found that a small GTPase Rab4b from a lepidopteran insect Helicoverpa armigera participates in gene transcription in the two pathways. The results show that RNA interference of Rab4b in larvae results in a decrease in glycogen levels, small pupae, abnormal metamorphic transition, or larval death...
November 1, 2012: Developmental Biology
Se Won Park, Christopher M Schonhoff, Cynthia R L Webster, M Sawkat Anwer
Cyclic AMP stimulates translocation of Na(+)/taurocholate cotransporting polypeptide (NTCP) from the cytosol to the sinusoidal membrane and multidrug resistance-associated protein 2 (MRP2) to the canalicular membrane. A recent study suggested that protein kinase Cδ (PKCδ) may mediate cAMP-induced translocation of Ntcp and Mrp2. In addition, cAMP has been shown to stimulate NTCP translocation in part via Rab4. The aim of this study was to determine whether cAMP-induced translocation of NTCP and MRP2 require kinase activity of PKCδ and to test the hypothesis that cAMP-induced activation of Rab4 is mediated via PKCδ...
September 1, 2012: American Journal of Physiology. Gastrointestinal and Liver Physiology
Burcu Hasdemir, Shilpi Mahajan, Nigel W Bunnett, Min Liao, Aditi Bhargava
CRF receptor 1 (CRF(1)), a key neuroendocrine mediator of the stress response, has two known agonists corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1). Here we report that endothelin-converting enzyme-1 (ECE-1) differentially degrades CRF and Ucn1; ECE-1 cleaves Ucn1, but not CRF, at critical residue Arginine-34/35', which is essential for ligand-receptor binding. At near K(D) agonist concentration (30 nm), both Ucn1- and CRF-mediated Ca(2+) mobilization are ECE-1 dependent. Interestingly, at high agonist concentration (100 nm), Ucn1-mediated Ca(2+) mobilization remains ECE-1 dependent, whereas CRF-mediated mobilization becomes independent of ECE-1 activity...
April 2012: Molecular Endocrinology
Alice Barbarin, Raymond Frade
The switch of human melanoma cell phenotype from non to highly tumorigenic and metastatic is triggered by the increase of procathepsin L secretion, which modifies the tumour microenvironment. The aim of the present study was to identify components involved in the regulation of procathepsin L secretion in melanoma cells. We focused on Rab family members, i.e. Rab3A, Rab4A, Rab4B, Rab5A, Rab8A, Rab11A, Rab27A and Rab33A, which are involved in distinct regulatory pathways. From analysis of mRNA and protein expression of these Rab components and their knockdown by specific siRNAs (small interfering RNAs) it emerged that Rab4A protein is involved in the regulation of procathepsin L secretion...
July 1, 2011: Biochemical Journal
Jung Ok Lee, Soo Kyung Lee, Jin Hee Jung, Ji Hae Kim, Ga Young You, Su Jin Kim, Sun Hwa Park, Kyung-Ok Uhm, Hyeon Soo Kim
Metformin is a major oral anti-diabetic drug and is known as an insulin sensitizer. However, the mechanism by which metformin acts is unclear. In this study, we found that AICAR, an AMPK activator, and metformin increased the expression of Rab4 mRNA and protein levels in skeletal muscle C2C12 cells. The promoter activity of Rab4 was increased by metformin in an AMPK-dependent manner. Metformin stimulated the phosphorylation of AS160, Akt substrate, and Rab GTPase activating protein (GAP), and also increased the phosphorylation of PKC-zeta, which is a critical molecule for glucose uptake...
April 2011: Journal of Cellular Physiology
Sharon Etzion, Yoram Etzion, Brian DeBosch, Peter A Crawford, Anthony J Muslin
Patients with diabetes mellitus can develop cardiac dysfunction in the absence of underlying coronary artery disease or hypertension; a condition defined as diabetic cardiomyopathy. Mice lacking the intracellular protein kinase Akt2 develop a syndrome that is similar to diabetes mellitus type 2. Expression profiling of akt2(-/-) myocardium revealed that Rab4a, a GTPase involved in glucose transporter 4 translocation and β-adrenergic receptor (βAR) recycling to the plasma membrane, was significantly induced...
December 2010: Journal of Molecular and Cellular Cardiology
Bin Xia, Alexandra Joubert, Benjamin Groves, Kevin Vo, Davin Ashraf, Derek Djavaherian, Jason Awe, Ying Xiong, Jacqueline Cherfils, Dzwokai Ma
We have previously shown that a subset of mDpy-30, an accessory subunit of the nuclear histone H3 lysine 4 methyltransferase (H3K4MT) complex, also localizes at the trans-Golgi network (TGN), where its recruitment is mediated by the TGN-localized ARF guanine nucleotide exchange factor (ArfGEF) BIG1. Depletion of mDpy-30 inhibits the endosome-to-TGN transport of internalized CIMPR receptors and concurrently promotes their accumulation at the cell protrusion. These observations suggest mDpy-30 may play a novel role at the crossroads of endosomal trafficking, nuclear transcription and adhesion/migration...
July 23, 2010: PloS One
Laura di Blasio, Sara Droetto, Jim Norman, Federico Bussolino, Luca Primo
The bidirectional communication between integrin alphavbeta3 and vascular endothelial growth factor (VEGF) receptors acts to integrate and coordinate endothelial cell (EC) activity during angiogenesis. However, the molecular mechanisms involved in this signaling crosstalk are only partially revealed. We have found that protein kinase D1 (PKD1) was activated by VEGF-A, but not by other angiogenic factors, and associated with alphavbeta3 integrin. Moreover, knockdown of PKD1 increased endocytosis of alphavbeta3 and reduced its return from endosomes to the plasma membrane leading to accumulation of the integrin in Rab5- and Rab4-positive endosomes...
August 2010: Traffic
Christopher T Eggers, Jenny C Schafer, James R Goldenring, Susan S Taylor
Dual-specific A-kinase-anchoring protein 2 (D-AKAP2/AKAP10), which interacts at its carboxyl terminus with protein kinase A and PDZ domain proteins, contains two tandem regulator of G-protein signaling (RGS) domains for which the binding partners have remained unknown. We show here that these RGS domains interact with Rab11 and GTP-bound Rab4, the first demonstration of RGS domains binding small GTPases. Rab4 and Rab11 help regulate membrane trafficking through the endocytic recycling pathways by recruiting effector proteins to specific membrane domains...
November 20, 2009: Journal of Biological Chemistry
Carina Hellberg, Christian Schmees, Susann Karlsson, Aive Ahgren, Carl-Henrik Heldin
Previous studies showed that loss of the T-cell protein tyrosine phosphatase (TC-PTP) induces Rab4a-dependent recycling of the platelet-derived growth factor (PDGF) beta-receptor in mouse embryonic fibroblasts (MEFs). Here we identify protein kinase C (PKC) alpha as the critical signaling component that regulates the sorting of the PDGF beta-receptor at the early endosomes. Down-regulation of PKC abrogated receptor recycling by preventing the sorting of the activated receptor into EGFP-Rab4a positive domains on the early endosomes...
June 2009: Molecular Biology of the Cell
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