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Wei-Yang Tao, Chun-Yang Wang, Yong-Hui Sun, Yong-Hui Su, Da Pang, Guo-Qiang Zhang
Abnormal expression of microRNAs plays important role in tumor metastasis. Migration and invasion of cancer cells accord for the metastasis and deterioration of breast cancer. However, the regulatory role of microRNAs in the invasion and migration of breast cancer cells has not completely understood yet. Here we found that microRNA-34c (miR-34c) was significantly downregulated in metastatic tissue of breast cancer. In vitro study showed that miR-34c negatively regulated GIT1 protein expression by binding to the 3'UTR of GIT1 mRNA...
2016: Journal of Cancer
M J Kim, J Biag, D M Fass, M C Lewis, Q Zhang, M Fleishman, S P Gangwar, M Machius, M Fromer, S M Purcell, S A McCarroll, G Rudenko, R T Premont, E M Scolnick, S J Haggarty
Although the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single-nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes...
July 26, 2016: Molecular Psychiatry
Mohammed Uddin, Giovanna Pellecchia, Bhooma Thiruvahindrapuram, Lia D'Abate, Daniele Merico, Ada Chan, Mehdi Zarrei, Kristiina Tammimies, Susan Walker, Matthew J Gazzellone, Thomas Nalpathamkalam, Ryan K C Yuen, Koenraad Devriendt, Géraldine Mathonnet, Emmanuelle Lemyre, Sonia Nizard, Mary Shago, Ann M Joseph-George, Abdul Noor, Melissa T Carter, Grace Yoon, Peter Kannu, Frédérique Tihy, Erik C Thorland, Christian R Marshall, Janet A Buchanan, Marsha Speevak, Dimitri J Stavropoulos, Stephen W Scherer
A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10(-15)) enrichment of critical-exons within rare CNVs in cases compared to controls...
2016: Scientific Reports
Laura J Smithson, David H Gutmann
As a critical regulator of cell growth, the mechanistic target of rapamycin (mTOR) protein operates as part of two molecularly and functionally distinct complexes. Herein, we demonstrate that mTOR complex molecular composition varies in different somatic tissues. In astrocytes and neural stem cells, we identified G-protein-coupled receptor kinase-interacting protein 1 (GIT1) as a novel mTOR-binding protein, creating a unique mTOR complex lacking Raptor and Rictor. Moreover, GIT1 binding to mTOR is regulated by AKT activation and is essential for mTOR-mediated astrocyte survival...
June 15, 2016: Genes & Development
Bobo Xie, Xin Fan, Yaqin Lei, Rongyu Chen, Jin Wang, Chunyun Fu, Shang Yi, Jingsi Luo, Shujie Zhang, Qi Yang, Shaoke Chen, Yiping Shen
BACKGROUND: Microdeletions at 17q11.2 often encompass NF1 gene, is the cause for NF1 microdeletion syndrome. Microdeletion at 17q11.2 without the involvement of NF1 gene is rarely reported. CASE PRESENTATION: Here we reported a patient carrying a novel de novo deletion at 17q11.2 adjacent to NF1 gene, who presented with developmental delay, short stature, postnatal microcephaly, underweight and dysmorphic features including flat facial profile, dolicocephaly, hypertelorism, short philtrum, flat nasal bridge and posteriorly rotated and low set ears...
2016: Molecular Cytogenetics
Guang-Zong Zhao, Long-Qiang Zhang, Yao Liu, Jun Fang, Hua-Zhuang Li, Ke-Hai Gao, Yun-Zhen Chen
The formation of fibrocartilage, cartilaginous and bony calluses is vital for bone healing following a fracture. Fibroblasts, chondrocytes and osteoblasts are critical functional cells that are involved in these three processes, respectively. Platelet‑derived growth factor (PDGF), a growth factor that is released from platelet particles and appears during the early stages at the site of fractures, is essential in bone healing via regulation of cell proliferation and differentiation. However, the effects of PDGF on the chondrocytes remain unclear...
July 2016: Molecular Medicine Reports
Wu Zhou, Xiaobo Li, Richard T Premont
The GIT proteins, GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf) small GTP-binding proteins, and function to limit the activity of Arf proteins. The PIX proteins, α-PIX and β-PIX (also known as ARHGEF6 and ARHGEF7, respectively), are guanine nucleotide exchange factors (activators) for the Rho family small GTP-binding protein family members Rac1 and Cdc42. Through their multi-domain structures, GIT and PIX proteins can also function as signaling scaffolds by binding to numerous protein partners...
May 15, 2016: Journal of Cell Science
Yi-Sheng Li, Li-Xia Qin, Jie Liu, Wei-Liang Xia, Jian-Ping Li, Hai-Lian Shen, Wei-Qiang Gao
GIT1, a G-protein-coupled receptor kinase interacting protein, has been reported to be involved in neurite outgrowth. However, the neurobiological functions of the protein remain unclear. In this study, we found that GIT1 was highly expressed in the nervous system, and its expression was maintained throughout all stages of neuritogenesis in the brain. In primary cultured mouse hippocampal neurons from GIT1 knockout mice, there was a significant reduction in total neurite length per neuron, as well as in the average length of axon-like structures, which could not be prevented by nerve growth factor treatment...
March 2016: Neural Regeneration Research
Wenwu Zhang, Youliang Huang, Susan J Gunst
KEY POINTS: In airway smooth muscle, tension development caused by a contractile stimulus requires phosphorylation of the 20 kDa myosin light chain (MLC), which activates crossbridge cycling and the polymerization of a pool of submembraneous actin. The p21-activated kinases (Paks) can regulate the contractility of smooth muscle and non-muscle cells, and there is evidence that this occurs through the regulation of MLC phosphorylation. We show that Pak has no effect on MLC phosphorylation during the contraction of airway smooth muscle, and that it regulates contraction by mediating actin polymerization...
September 1, 2016: Journal of Physiology
Markéta Černohorská, Vadym Sulimenko, Zuzana Hájková, Tetyana Sulimenko, Vladimíra Sládková, Stanislav Vinopal, Eduarda Dráberová, Pavel Dráber
Microtubule nucleation from γ-tubulin complexes, located at the centrosome, is an essential step in the formation of the microtubule cytoskeleton. However, the signaling mechanisms that regulate microtubule nucleation in interphase cells are largely unknown. In this study, we report that γ-tubulin is in complexes containing G protein-coupled receptor kinase-interacting protein 1 (GIT1), p21-activated kinase interacting exchange factor (βPIX), and p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) in various cell lines...
June 2016: Biochimica et Biophysica Acta
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
Zoltan Nagy, Kieran Wynne, Alexander von Kriegsheim, Stepan Gambaryan, Albert Smolenski
Endothelial cells release prostacyclin (PGI2) and nitric oxide (NO) to inhibit platelet functions. PGI2 and NO effects are mediated by cyclic nucleotides, cAMP- and cGMP-dependent protein kinases (PKA, PKG), and largely unknown PKA and PKG substrate proteins. The small G-protein Rac1 plays a key role in platelets and was suggested to be a target of cyclic nucleotide signaling. We confirm that PKA and PKG activation reduces Rac1-GTP levels. Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets...
December 11, 2015: Journal of Biological Chemistry
Jeng-Shou Chang, Chia-Yi Su, Wen-Hsuan Yu, Wei-Jiunn Lee, Yu-Peng Liu, Tsung-Ching Lai, Yi-Hua Jan, Yi-Fang Yang, Chia-Ning Shen, Jin-Yuh Shew, Jean Lu, Chih-Jen Yang, Ming-Shyan Huang, Pei-Jung Lu, Yuan-Feng Lin, Min-Liang Kuo, Kuo-Tai Hua, Michael Hsiao
G-protein-coupled receptor kinase interacting protein 1 (GIT1) is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/PIX forming a functional protein complex that contributes to Rac1/Cdc42 activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in non-small-cell lung cancer (NSCLC) and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility...
November 3, 2015: Oncotarget
Silvia Gramolelli, Magdalena Weidner-Glunde, Bizunesh Abere, Abel Viejo-Borbolla, Kiran Bala, Jessica Rückert, Elisabeth Kremmer, Thomas F Schulz
Kaposi's sarcoma (KS), caused by Kaposi's sarcoma herpesvirus (KSHV), is a highly vascularised tumour of endothelial origin. KSHV infected endothelial cells show increased invasiveness and angiogenesis. Here, we report that the KSHV K15 protein, which we showed previously to contribute to KSHV-induced angiogenesis, is also involved in KSHV-mediated invasiveness in a PLCγ1-dependent manner. We identified βPIX, GIT1 and cdc42, downstream effectors of PLCγ1 in cell migration, as K15 interacting partners and as contributors to KSHV-triggered invasiveness...
August 2015: PLoS Pathogens
Jiefang Li, Qinrong Wang, Ruiling Wen, Jieman Liang, Xiaoling Zhong, Wei Yang, Dongxiang Su, Jun Tang
Non-small-cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide with a poor 5-year survival rate. Recent studies indicated that miRNAs have been involved in the tumorigenic driver pathways in NSCLC, but the relevant molecular mechanisms are not well-understood. In this study, we investigated the biological functions and molecular mechanisms of miR-138 in human NSCLC. The effects of miR-138 on the NSCLC cell growth and epithelial-mesenchymal transition (EMT) were first examined...
December 2015: Journal of Cellular and Molecular Medicine
Xiaolin Lu, Fangning Wan, Hailiang Zhang, Guohai Shi, Dingwei Ye
Integrins play an important role in cancer growth and metastasis. This study aimed at determining the predictive ability of integrins and associated genes identified through molecular network in clear cell renal cell carcinoma. A total of 525 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohorts were collected in this study. The expression profile of integrins and related genes were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, gender, tumor size, tumor node metastasis (TNM), tumor grade, stage, laterality, and overall survival were collected...
January 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Won Mah
Cross-talk between the thalamus and cortex has been implicated in attention but its pathogenic role in attention-deficit/hyperactivity disorder (ADHD) remains unknown. Here, I demonstrate that Git1 (-/-) mice, previously proposed as an animal model for ADHD, show abnormal theta oscillation in the thalamus. Multi-electrode recordings revealed that Git1 (-/-) mice have hyper-synchrony of neural activities between the thalamus and cortex. The abnormal thalamic oscillation and thalamocortical synchrony in Git1 (-/-) mice were markedly reduced by amphetamine...
June 2015: Experimental Neurobiology
Marieke Klein, Monique van der Voet, Benjamin Harich, Kimm J E van Hulzen, A Marten H Onnink, Martine Hoogman, Tulio Guadalupe, Marcel Zwiers, Johanne M Groothuismink, Alicia Verberkt, Bonnie Nijhof, Anna Castells-Nobau, Stephen V Faraone, Jan K Buitelaar, Annette Schenck, Alejandro Arias-Vasquez, Barbara Franke
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N = 19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N = 225), and (3) the Brain Imaging Genetics cohort (BIG, N = 1,300)...
June 10, 2015: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Soo-Yeon Lim, Won Mah
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting approximately 5% of children. However, the neural mechanisms underlying its development and treatment are yet to be elucidated. In this study, we report that an ADHD mouse model, which harbors a deletion in the Git1 locus, exhibits severe astrocytosis in the globus pallidus (GP) and thalamic reticular nucleus (TRN), which send modulatory GABAergic inputs to the thalamus. A moderate level of astrocytosis was displayed in other regions of the basal ganglia pathway, including the ventrobasal thalamus and cortex, but not in other brain regions, such as the caudate putamen, basolateral amygdala, and hippocampal CA1...
June 2015: Molecules and Cells
Vadym Sulimenko, Zuzana Hájková, Markéta Černohorská, Tetyana Sulimenko, Vladimíra Sládková, Lubica Dráberová, Stanislav Vinopal, Eduarda Dráberová, Pavel Dráber
Ag-mediated activation of mast cells initiates signaling events leading to Ca(2+) response, release of allergic mediators from cytoplasmic granules, and synthesis of cytokines and chemokines. Although microtubule rearrangement during activation has been described, the molecular mechanisms that control their remodeling are largely unknown. Microtubule nucleation is mediated by complexes that are formed by γ-tubulin and γ-tubulin complex proteins. In this study, we report that, in bone marrow-derived mast cells (BMMCs), γ-tubulin interacts with p21-activated kinase interacting exchange factor β (βPIX) and G protein-coupled receptor kinase-interacting protein (GIT)1...
May 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
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