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Maria Haanpää, Helena Schlecht, Gauri Batra, Jill Clayton-Smith, Sofia Douzgou
Kabuki syndrome is a rare developmental disorder characterized by typical facial features, postnatal growth deficiency, mild to moderate intellectual disability, and minor skeletal anomalies. It is caused by mutations of the KMT2D and KDM6A genes while recently RAP1A and RAP1B mutations have been shown to rarely contribute to the pathogenesis. We report two patients' presentation of Kabuki syndrome caused by different KMT2D mutations, both including an interrupted/bipartite clavicle. The clinical diagnosis of Kabuki syndrome may be challenging, especially in younger patients and we suggest that the observation of a bipartite clavicle may be an additional diagnostic clue to prompt investigation for Kabuki syndrome...
March 3, 2017: American Journal of Medical Genetics. Part A
Verena Supper, Ingrid Hartl, Cyril Boulègue, Anna Ohradanova-Repic, Hannes Stockinger
Numerous publications have addressed CD147 as a tumor marker and regulator of cytoskeleton, cell growth, stress response, or immune cell function; however, the molecular functionality of CD147 remains incompletely understood. Using affinity purification, mass spectrometry, and phosphopeptide enrichment of isotope-labeled peptides, we examined the dynamic of the CD147 microenvironment and the CD147-dependent phosphoproteome in the Jurkat T cell line upon treatment with T cell stimulating agents. We identified novel dynamic interaction partners of CD147 such as CD45, CD47, GNAI2, Lck, RAP1B, and VAT1 and, furthermore, found 76 CD147-dependent phosphorylation sites on 57 proteins...
February 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Zhao Jia, Yang Yang, Zhu Dengyan, Zhang Chunyang, Liu Donglei, Wu Kai, Zhao Song
RAP1B is a small GTPase, which regulates multiple cellular processes. Up-regulation of RAP1B has been observed in several cancer types. Although previous study has shown that miR-518 inhibited the proliferation and invasion of esophageal squamous cell carcinoma (ESCC) cells possibly by targeting RAP1B, the expression pattern and the functions of RAP1B in ESCC are not fully understood. Here, we have fund that the expression of RAP1B was up-regulated in ESCC clinical samples. Gain-of-function and loss-of-function assays demonstrated that RAP1B promoted the growth, migration and metastasis of the ESCC cells...
May 5, 2017: Gene
Maho Takahashi, Yanping Li, Tara J Dillon, Philip J S Stork
Cyclic adenosine monophosphate (cAMP) is an important mediator of hormonal stimulation of cell growth and differentiation through its activation of the extracellular signal-regulated kinase (ERK) cascade. Two small G proteins, Ras and Rap1 have been proposed to mediate this activation. Using HEK293 cells as a model system, we have recently shown that both Ras and Rap1 are required for cAMP signaling to ERKs. However, cAMP-dependent Ras signaling to ERKs is transient and rapidly terminated by PKA phosphorylation of the Raf isoforms C-Raf and B-Raf...
January 27, 2017: Journal of Biological Chemistry
W Zhu, H Shen, J-G Zhang, L Zhang, Y Zeng, H-L Huang, Y-C Zhao, H He, Y Zhou, K-H Wu, Q Tian, L-J Zhao, F-Y Deng, H-W Deng
In male Caucasians with discordant hip bone mineral density (BMD), we applied the subcellular separation and proteome profiling to investigate the monocytic cytosol. Three BMD-associated proteins (ALDOA, MYH14, and Rap1B) were identified based on multiple omics evidence, and they may influence the pathogenic mechanisms of osteoporosis by regulating the activities of monocytes. INTRODUCTION: Osteoporosis is a serious public health problem, leading to significant mortality not only in aging females but also in males...
November 14, 2016: Osteoporosis International
Jeannine Muller-Greven, SoonJeung Kim, Prasanta K Hota, Yufeng Tong, Susmita Borthakur, Matthias Buck
Plexins are unique, as they are the first example of a transmembrane receptor that interacts directly with small GTPases, a family of proteins that are essential for cell motility and proliferation/survival. We and other laboratories have determined the structure of the Rho GTPase-binding domain (RBD) of several plexins and also of the entire intracellular region of plexin-B1. Structures of plexin complexes with Rho GTPases, Rac1 and Rnd1, and a structure with a Ras GTPase, Rap1b, have also been solved. The relationship between plexin-Rho and plexin-Ras interactions is still unclear and in vitro biophysical experiments that characterize the protein interactions of purified components play an important role in advancing our understanding of the molecular mechanisms that underlie the function of plexin...
2017: Methods in Molecular Biology
Jessica M Wilson, Jeremy W Prokop, Ellen Lorimer, Elizabeth Ntantie, Carol L Williams
Two isoforms of the small GTPase Rap1, Rap1A and Rap1B, participate in cell adhesion; Rap1A promotes steady state adhesion, while Rap1B regulates dynamic changes in cell adhesion. These events depend on the prenylation of Rap1, which promotes its membrane localization. Here, we identify previously unsuspected differences in the regulation of prenylation of Rap1A versus Rap1B, due in part to their different phosphorylation-dependent interactions with the chaperone protein SmgGDS-607. Previous studies indicate that the activation of Gαs protein-coupled receptors (GPCRs) phosphorylates S-179 and S-180 in the polybasic region (PBR) of Rap1B, which inhibits Rap1B binding to SmgGDS-607 and diminishes Rap1B prenylation and membrane localization...
December 4, 2016: Journal of Molecular Biology
Cheng Wang, Caiyun Wu, Qi Yang, Meng Ding, Jinsha Zhong, Chen-Yu Zhang, Jingping Ge, Junjun Wang, Chunni Zhang
The incidence and mortality rate of renal cell carcinoma (RCC) have been significantly increasing; however, the mechanisms involved in RCC development and progression are unclear. In this study, we found that miR-28-5p was decreased in RCC tumor specimens and several renal carcinoma cell lines. By using a combination of luciferase reporter assays and western blotting, we identified RAP1B, a Ras-related small GTP-binding oncoprotein implicated in a variety of tumors, as a direct target of miR-28-5p in RCC. The RAP1B protein level was increased in RCC tumor specimens and renal carcinoma cell lines, and this was inversely correlated with miR-28-5p expression...
November 8, 2016: Oncotarget
Yazhou Li, Yang Liu, Feiyu Shi, Liang Cheng, Junjun She
Gastric cancer (GC) is the fourth most common malignancy and the second leading cause of cancer mortality around the world. However, the regulatory mechanisms of GC tumorigenesis and cancer cell motility are completely unknown. We investigated the role of a RAS-related protein (Rap1b) in the progression of GC. Our results showed that the expression of Rap1b is aberrantly upregulated in GC tissue samples and human GC cell lines, and the high expression of Rap1b indicated a positive correlation with poor prognosis in patients with GC...
2016: Oncology Research
Haocong Zhang, Yan Wang
BACKGROUND: Spinal cord injury (SCI) is highly related to the devastating sensory and motor dysfunction. METHODS: The GSE45006 gene expression profile dataset was downloaded from Gene Expression Omnibus, which was collected from 24 rats including 20 animals with injured T7 spinal cords using an aneurysm clip impact-compression injury model and killed after 1 day, 3 days, 1 week, 2 weeks, and 8 weeks and four sham-operated rats. Differentially expressed genes (DEGs) between the injured rats at each time point and the sham-operated rats were screened...
September 15, 2016: Journal of Orthopaedic Surgery and Research
Peter M Benz, Hebatullah Laban, Joana Zink, Lea Günther, Ulrich Walter, Stepan Gambaryan, Karim Dib
BACKGROUND: Vasodilator-Stimulated Phosphoprotein (VASP) is involved in the inhibition of agonist-induced platelet aggregation by cyclic nucleotides and the adhesion of platelets to the vascular wall. αIIbβ3 is the main integrin responsible for platelet activation and Rap1b plays a key role in integrin signalling. We investigated whether VASP is involved in the regulation of Rap1b in platelets since VASP-null platelets exhibit augmented adhesion to endothelial cells in vivo. METHODS: Washed platelets from wild type and VASP-deficient mice were stimulated with thrombin, the purinergic receptors agonist ADP, or the thromboxane A2 receptor agonist U46619 and Rap1b activation was measured using the GST-RalGDS-RBD binding assay...
September 13, 2016: Cell Communication and Signaling: CCS
Haibo Wang, Xiaokun Han, Colin A Bretz, Silke Becker, Deeksha Gambhir, George W Smith, R Jude Samulski, Erika S Wittchen, Lawrence A Quilliam, Magdalena Chrzanowska-Wodnicka, M Elizabeth Hartnett
To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV), self-complementary adeno-associated virus 2 (scAAV2) with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con) or constitutively active Rap1a (scAAV2-CARap1a) showed strong GFP at the 5 × 10(8) viral particle/µl dose 5 weeks later without altering retinal morphology or function...
2016: Molecular Therapy. Methods & Clinical Development
S L K Bowers, P R Norden, G E Davis
During capillary network formation, ECs establish interconnecting tubes with defined lumens that reside within vascular guidance tunnels (physical spaces generated during EC tubulogenesis). Pericytes are recruited to EC tubes within these tunnels and capillary basement membrane deposition occurs to facilitate tube maturation. Here, we discuss molecular mechanisms controlling EC tubulogenesis demonstrating the involvement of integrins, MT1-MMP, extracellular matrix, Cdc42, Rac1, Rac2, k-Ras, Rap1b, and key downstream effectors including Pak2, Pak4, IQGAP1, MRCKβ, and Rasip1...
2016: Advances in Pharmacology
Paulina B Szklanna, Martina Foy, Kieran Wynne, Dwayne Byrne, Patricia B Maguire
Proteomic studies have facilitated the identification of proteins associated with the detergent-resistant membrane (DRM) fraction in a variety of cell types. Here, we have undertaken label-free quantitative (LFQ) proteomic profiling of the proteins associated with detergent-resistant plasma and internal membranes from resting and activated platelets. One hundred forty-one proteins were identified and raw data is available via ProteomeXchange with identifier PXD002554. The proteins identified include a myriad of important platelet signaling and trafficking proteins including Rap1b, Src, SNAP-23, syntaxin-11, and members of the previously unattributed Ragulator complex...
September 2016: Proteomics
Young Ou, Gordon Chan, Jeremy Zuo, Jerome B Rattner, Frans A van der Hoorn
The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration...
July 15, 2016: Journal of Biological Chemistry
Bhavin Shah, Daniela Lutter, Magdalena L Bochenek, Katsuhiro Kato, Yaroslav Tsytsyura, Natalia Glyvuk, Akira Sakakibara, Jürgen Klingauf, Ralf H Adams, Andreas W Püschel
The establishment of a polarized morphology is essential for the development and function of neurons. During the development of the mammalian neocortex, neurons arise in the ventricular zone (VZ) from radial glia cells (RGCs) and leave the VZ to generate the cortical plate (CP). During their migration, newborn neurons first assume a multipolar morphology in the subventricular zone (SVZ) and lower intermediate zone (IZ). Subsequently, they undergo a multi-to-bipolar (MTB) transition to become bipolar in the upper IZ by developing a leading process and a trailing axon...
2016: PloS One
Roman Tatura, Malte Buchholz, Dennis W Dickson, John van Swieten, Catriona McLean, Günter Höglinger, Ulrich Müller
Progressive supranuclear palsy is a sporadic neurodegenerative disorder. Genetic, environmental, and possibly epigenetic factors contribute to disease. In order to better understand the potential role of epigenetic changes in progressive supranuclear palsy, we investigated whether some microRNAs and their target genes are dysregulated. We analyzed expression of 372 well-characterized microRNAs in forebrains of a total of 40 patients and of 40 controls using TaqMan arrays and SYBR Green quantitative real-time PCR...
July 2016: Neurogenetics
Fangyuan Zou, Rurong Mao, Liyan Yang, Shengchao Lin, Kecheng Lei, Yuanhong Zheng, Yue Ding, Peng Zhang, Guoxiang Cai, Xin Liang, Jianwen Liu
miR-139-5p, which has been reported to be underexpressed in several types of cancer, is associated with tumorigenesis by participating in various biological processes via the modulation of different target genes. In the present study, we analyzed mice deficient in miR-139-5p, aiming to investigate its role in intestinal inflammation and colitis-associated colorectal cancer. We show that miR-139-5p knockout (KO) mice are highly susceptible to colitis and colon cancer, accompanied by elevated proliferation and decreased apoptosis, as well as an increased production of inflammatory cytokines, chemokines and tumorigenic factors...
April 2016: FEBS Journal
Michael E Cahill, Rosemary C Bagot, Amy M Gancarz, Deena M Walker, HaoSheng Sun, Zi-Jun Wang, Elizabeth A Heller, Jian Feng, Pamela J Kennedy, Ja Wook Koo, Hannah M Cates, Rachael L Neve, Li Shen, David M Dietz, Eric J Nestler
Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure...
February 3, 2016: Neuron
Pieter R Norden, Dae Joong Kim, David M Barry, Ondine B Cleaver, George E Davis
A critical and understudied property of endothelial cells is their ability to form lumens and tube networks. Although considerable information has been obtained concerning these issues, including the role of Cdc42 and Rac1 and their effectors such as Pak2, Pak4, Par6b, and co-regulators such as integrins, MT1-MMP and Par3; many key questions remain that are necessary to elucidate molecular and signaling requirements for this fundamental process. In this work, we identify new small GTPase regulators of EC tubulogenesis including k-Ras, Rac2 and Rap1b that act in conjunction with Cdc42 as well as the key downstream effectors, IQGAP1, MRCKβ, beta-Pix, GIT1, and Rasip1 (which can assemble into multiprotein complexes with key regulators including α2β1 integrin and MT1-MMP)...
2016: PloS One
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