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Didi Wu, Dahai Yu, Xiuxia Wang, Bingzhi Yu
: In mouse fertilized eggs, correct assembly and distribution of the actin cytoskeleton are intimately related to cleavage in early-stage embryos. However, in mouse fertilized eggs, mechanisms and involved factors responsible for regulating the actin cytoskeleton are poorly defined. In this study, mTORC2, PKB/Akt and Girdin were found to modulate division of mouse fertilized eggs by regulating distribution of the actin cytoskeleton. RNA interference (RNAi)-mediated depletion of mTORC2, Akt1 or Girdin disrupted F-actin rearrangement and strongly inhibited egg development...
September 25, 2016: Cell Proliferation
Xue-Song Wu, Tian-Hao Bao, Yang Ke, De-Yun Sun, Zhi-Tian Shi, Hao-Ran Tang, Lin Wang
Histidine triad nucleotide-binding protein 1 (Hint1) is a haploinsufficient tumor suppressor gene. Its role in cancer cell migration has not been previously speculated. In the current study, we examined the expression of Hint1 in metastatic and non-metastatic lymph nodes of hepatocellular carcinoma (HCC) patients and further elucidated the effect of Hint1 expression on girdin expression and phosphorylation of AKT and ERK1/2 and on the migration of HCC cells in vitro. Expression of Hint1 and girdin in primary HCC tissues and metastatic and non-metastatic lymph nodes was determined by RT-PCR assays...
September 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Inna V Nechipurenko, Anique Olivier-Mason, Anna Kazatskaya, Julie Kennedy, Ian G McLachlan, Maxwell G Heiman, Oliver E Blacque, Piali Sengupta
Primary cilia are ubiquitous sensory organelles that mediate diverse signaling pathways. Cilia position on the cell surface is determined by the location of the basal body (BB) that templates the cilium. The mechanisms that regulate BB positioning in the context of ciliogenesis are largely unknown. Here we show that the conserved signaling and scaffolding protein Girdin localizes to the proximal regions of centrioles and regulates BB positioning and ciliogenesis in Caenorhabditis elegans sensory neurons and human RPE-1 cells...
September 12, 2016: Developmental Cell
Vijay Gupta, Deepali Bhandari, Anthony Leyme, Nicolas Aznar, Krishna K Midde, I-Chung Lo, Jason Ear, Ingrid Niesman, Inmaculada López-Sánchez, Juan Bautista Blanco-Canosa, Mark von Zastrow, Mikel Garcia-Marcos, Marilyn G Farquhar, Pradipta Ghosh
We previously showed that guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein (GIV), a guanine-nucleotide exchange factor (GEF), transactivates Gα activity-inhibiting polypeptide 1 (Gαi) proteins in response to growth factors, such as EGF, using a short C-terminal motif. Subsequent work demonstrated that GIV also binds Gαs and that inactive Gαs promotes maturation of endosomes and shuts down mitogenic MAPK-ERK1/2 signals from endosomes. However, the mechanism and consequences of dual coupling of GIV to two G proteins, Gαi and Gαs, remained unknown...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ying Dunkel, Kexin Diao, Nicolas Aznar, Lee Swanson, Lawrence Liu, Wenhong Zhu, Xiaoyi Mi, Pradipta Ghosh
Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0...
July 20, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ping Jiang, Ya-Li Ren, Jia-Liang Li, Jun Luo
Cervical cancer is a major cause of mortality in females worldwide, with the majority of cases reported in developing countries. The molecular mechanisms of this disease are unclear. However, increasing evidence indicates that the expression or overexpression of Girdin is associated with a poor prognosis in a variety of cancer types. Therefore, the aim of the current study was to evaluate the potential association between Girdin expression, and malignant properties of cervical cancer lesions and HeLa cells...
April 2016: Oncology Letters
Pradipta Ghosh, Jeanne Tie, Andrea Muranyi, Shalini Singh, Patrick Brunhoeber, Katherine Leith, Rebecca Bowermaster, Zhiming Liao, Yifei Zhu, Bonnie LaFleur, Ben Tran, Jayesh Desai, Ian Jones, Matthew Croxford, Rodrigo Jover, Ajay Goel, Paul Waring, Song Hu, Volker Teichgraber, Ulrich-Peter Rohr, Ruediger Ridder, Kandavel Shanmugam, Peter Gibbs
PURPOSE: Prognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. EXPERIMENTAL DESIGN: Expression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data...
July 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Atsushi Enomoto, Takuya Kato, Naoya Asai, Masahide Takahashi
In embryonal development and pathogenesis of diseases, cells often get connected and form small groups to undergo "collective migration", rather than spread out individually. The examples include the migration of neural crest cells and neuroblasts during development and the invasion of cancers in surrounding stroma, indicating the importance and significance of collective behavior of cells in the body. Recent studies have revealed the mechanisms for collective cell migration, which had seemed not to be the subject of traditional cell biology on single cells in culture...
March 2016: Nihon Rinsho. Japanese Journal of Clinical Medicine
Norimichi Itoh, Atsushi Enomoto, Taku Nagai, Masahide Takahashi, Kiyofumi Yamada
It is well known that synaptic plasticity is the cellular mechanism underlying learning and memory. Activity-dependent synaptic changes in electrical properties and morphology, including synaptogenesis, lead to alterations of synaptic strength, which is associated with long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling is involved in learning and memory formation by regulating synaptic plasticity. The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is one of the key signaling cascades downstream BDNF/TrkB and is believed to modulate N-methyl-d-aspartate (NMDA) receptor-mediated synaptic plasticity...
July 1, 2016: Reviews in the Neurosciences
Michael S Nahorski, Masato Asai, Emma Wakeling, Alasdair Parker, Naoya Asai, Natalie Canham, Susan E Holder, Ya-Chun Chen, Joshua Dyer, Angela F Brady, Masahide Takahashi, C Geoffrey Woods
Progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a rare Mendelian phenotype comprising severe retardation, early onset epileptic seizures, optic nerve/cerebellar atrophy, pedal oedema, and early death. Atypical cases are often known as PEHO-like, and there is an overlap with 'early infantile epileptic encephalopathy'. PEHO is considered to be recessive, but surprisingly since initial description in 1991, no causative recessive gene(s) have been described. Hence, we report a multiplex consanguineous family with the PEHO phenotype where affected individuals had a homozygous frame-shift deletion in CCDC88A (c...
April 2016: Brain: a Journal of Neurology
Jorge Barbazan, Ying Dunkel, Hongying Li, Ulrich Nitsche, Klaus-Peter Janssen, Karen Messer, Pradipta Ghosh
The consequence of a loss of balance between G-protein activation and deactivation in cancers has been interrogated by studying infrequently occurring mutants of trimeric G-protein α-subunits and GPCRs. Prior studies on members of a newly identified family of non-receptor guanine nucleotide exchange factors (GEFs), GIV/Girdin, Daple, NUCB1 and NUCB2 have revealed that GPCR-independent hyperactivation of trimeric G proteins can fuel metastatic progression in a variety of cancers. Here we report that elevated expression of each GEF in circulating tumor cells (CTCs) isolated from the peripheral circulation of patients with metastatic colorectal cancer is associated with a shorter progression-free survival (PFS)...
2016: Scientific Reports
Xiaoze Wang, Atsushi Enomoto, Naoya Asai, Takuya Kato, Masahide Takahashi
Clinical pathologists have long been aware that in many types of human malignant tumors, the cells are often connected and form groups of various sizes or "nests". In this way, they achieve "collective invasion" into the surrounding stroma, rather than spreading out individually. Such collective behavior is also a common feature of migration during embryonic and postnatal developmental stages, suggesting there are advantages gained by collective cell migration in the organisms. Recent studies have revealed the mechanisms underlying the collective invasion of cancer cells...
April 2016: Pathology International
Endica Radic Hozo, Goran Sucic, Ivan Zaja
INTRODUCTION: The occurrence of burnout syndrome (BS) has been recognized in many professions (pilots, firefighters, police officers, doctors…) that during their work are subjected to high levels of stress. For educators in preschool institutions stress level is very high thus creating the possibility of developing BS. MATERIAL AND METHODS: For this research is selected preschool institution - kindergarten "Radost" (Joy) in Split, in which by use of questionnaires (modified scale by Freudenberger and modified scales by Girdin, Everly and Dusek) during 2014 among educators (100 respondents) is conducted a survey regarding the frequency of burnout syndrome...
December 2015: Materia Socio-medica
Anthony Leyme, Arthur Marivin, Mikel Garcia-Marcos
Activation of the tyrosine kinase focal adhesion kinase (FAK) upon cell stimulation by the extracellular matrix initiates integrin outside-in signaling. FAK is directly recruited to active integrins, which enhances its kinase activity and triggers downstream signaling like activation of PI3K. We recently described that Gα-interacting, vesicle-associated protein (GIV), a protein up-regulated in metastatic cancers, is also required for outside-in integrin signaling. More specifically, we found that GIV is a non-receptor guanine nucleotide exchange factor that activates trimeric G proteins in response to integrin stimulation to enhance PI3K signaling and tumor cell migration...
April 8, 2016: Journal of Biological Chemistry
Nicolas Aznar, Nicholas Kalogriopoulos, Krishna K Midde, Pradipta Ghosh
Canonical signal transduction via heterotrimeric G proteins is spatially and temporally restricted, that is, triggered exclusively at the plasma membrane (PM), only by agonist activation of G protein-coupled receptors (GPCRs) via a process that completes within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a non-canonical pathway for activation of heterotrimeric G proteins by the non-receptor guanidine-nucleotide exchange factor (GEF), GIV/Girdin. This pathway has distinctive temporal and spatial features and an unusual profile of receptor engagement: diverse classes of receptors, not just GPCRs can engage with GIV to trigger such activation...
April 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Ke Cao, Jingjing Li, Yong Zhao, Qi Wang, Qinghai Zeng, Siqi He, Li Yu, Jianda Zhou, Peiguo Cao
miR-101 is considered to play an important role in hepato-cellular carcinoma (HCC), but the underlying molecular mechanism remains to be elucidated. Here, we aimed to confirm whether Girdin is a target gene of miR-101 and determine the tumor suppressor of miR-101 through Girdin pathway. In our previous studies, we firstly found Girdin protein was overexpressed in HCC tissues, and it closely correlated to tumor size, T stage, TNM stage and Edmondson-Steiner stage of HCC patients. After specific small interfering RNA of Girdin was transfected into HepG2 and Huh7...
February 2016: Molecules and Cells
Masahide Takahashi, Naoya Asai, Atsushi Enomoto
No abstract text is available yet for this article.
2015: Oncoscience
Inmaculada Lopez-Sanchez, Nicholas Kalogriopoulos, I-Chung Lo, Firooz Kabir, Krishna K Midde, Honghui Wang, Pradipta Ghosh
GIV/Girdin is a multimodular signal transducer and a bona fide metastasis-related protein. As a guanidine exchange factor (GEF), GIV modulates signals initiated by growth factors (chemical signals) by activating the G protein Gαi. Here we report that mechanical signals triggered by the extracellular matrix (ECM) also converge on GIV-GEF via β1 integrins and that focal adhesions (FAs) serve as the major hubs for mechanochemical signaling via GIV. GIV interacts with focal adhesion kinase (FAK) and ligand-activated β1 integrins...
December 1, 2015: Molecular Biology of the Cell
Deepali Bhandari, Inmaculada Lopez-Sanchez, Andrew To, I-Chung Lo, Nicolas Aznar, Anthony Leyme, Vijay Gupta, Ingrid Niesman, Adam L Maddox, Mikel Garcia-Marcos, Marilyn G Farquhar, Pradipta Ghosh
Signals propagated by receptor tyrosine kinases (RTKs) can drive cell migration and proliferation, two cellular processes that do not occur simultaneously--a phenomenon called "migration-proliferation dichotomy." We previously showed that epidermal growth factor (EGF) signaling is skewed to favor migration over proliferation via noncanonical transactivation of Gαi proteins by the guanine exchange factor (GEF) GIV. However, what turns on GIV-GEF downstream of growth factor RTKs remained unknown. Here we reveal the molecular mechanism by which phosphorylation of GIV by cyclin-dependent kinase 5 (CDK5) triggers GIV's ability to bind and activate Gαi in response to growth factors and modulate downstream signals to establish a dichotomy between migration and proliferation...
September 1, 2015: Proceedings of the National Academy of Sciences of the United States of America
Pradipta Ghosh
Most common diseases, e.g., cancer are driven by not one, but multiple cell surface receptors that trigger and sustain a pathologic signaling network. The largest fraction of therapeutic agents that target individual receptors/pathways eventually fail due to the emergence of compensatory mechanisms that reestablish the pathologic network. Recently, a rapidly emerging paradigm has revealed GIV/Girdin as a central platform for receptor cross-talk which integrates signals downstream of a myriad of cell surface receptors, and modulates several key pathways within downstream signaling network, all via non-canonical activation of trimeric G proteins...
July 2015: Aging
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