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Vincent DiGiacomo, Alain Ibáñez de Opakua, Maria P Papakonstantinou, Lien T Nguyen, Nekane Merino, Juan B Blanco-Canosa, Francisco J Blanco, Mikel Garcia-Marcos
Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Gαi. GIV expression promotes metastasis and disruption of its binding to Gαi blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Gαi-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly "druggable" targets requiring case-by-case validation...
August 17, 2017: Scientific Reports
Jong-Sun Choi, Kyung Hee Kim, Ensel Oh, Young Kee Shin, Jinwon Seo, Seok-Hyung Kim, Sarah Park, Yoon-La Choi
Girdin is an actin-binding Akt substrate that is an integral component of the PI3K/Akt signalling pathway. However, the clinicopathological significance of Girdin expression in breast cancer has not been clarified. The purpose of this study was to characterise the clinicopathological implication of Girdin expression in breast cancer. Immunohistochemistry-based protein expression analyses of 892 human breast cancer tissues showed that Girdin was expressed in 289 (32.4%) cases. Girdin expression was significantly associated with larger tumour size, frequent lymph node invasion, advanced cancer stage, and expression of oestrogen and progesterone receptors...
August 14, 2017: Pathology
Li Yu, Yifan Sun, Jingjing Li, Yan Wang, Yuxing Zhu, Yong Shi, Xiaojun Fan, Jianda Zhou, Ying Bao, Jie Xiao, Ke Cao, Peiguo Cao
BACKGROUND: Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. METHODS: A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression...
August 15, 2017: Journal of Experimental & Clinical Cancer Research: CR
Hongbin Wang, Jiajun Zhang, Ming Zhang, Li Wei, Hong Chen, Zhigao Li
Breast cancer has one of the highest incidences in females worldwide. Girdin is a novel actin‑binding protein, that induces cell migration and angiogenesis. However, a systematic study of Girdin function in distinct subtypes of breast cancer has not been reported to date. Therefore, the present study aimed to investigate the role of Girdin on cell proliferation, migration and angiogenesis in different subtypes of breast cancer. For this purpose, the breast epithelial MCF‑7, breast ductal T47D and breast metastatic MDA‑MB‑231 cancer cell lines were selected...
September 2017: Molecular Medicine Reports
Yang Ke, Tianhao Bao, Qixin Zhou, Yan Wang, Jiayun Ge, Bimang Fu, Xuesong Wu, Haoran Tang, Zhitian Shi, Xuefen Lei, Cheng Zhang, Yuqi Tan, Haotian Chen, Zhitang Guo, Lin Wang
Invadopodium formation is a crucial early event of invasion and metastasis of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying regulation of invadopodia remain elusive. This study aimed to investigate the potential role of discs large homolog 5 (Dlg5) in invadopodium formation and function in HCC. We found that Dlg5 expression was significantly lower in human HCC tissues and cell lines than adjacent nontumor tissues and liver cells. Lower Dlg5 expression was associated with advanced stages of HCC, and poor overall and disease-free survival of HCC patients...
July 15, 2017: International Journal of Cancer. Journal International du Cancer
Daisuke Kuga, Kaori Ushida, Shinji Mii, Atsushi Enomoto, Naoya Asai, Masato Nagino, Masahide Takahashi, Masato Asai
Tuft cells (TCs) are minor components of gastrointestinal epithelia, characterized by apical tufts and spool-shaped somas. The lack of reliable TC-markers has hindered the elucidation of its role. We developed site-specific and phosphorylation-status-specific antibodies against Girdin at tyrosine-1798 (pY1798) and found pY1798 immunostaining of mouse jejunum clearly depicted epithelial cells closely resembling TCs. This study aimed to validate pY1798 as a TC-marker. Double-fluorescence staining of intestines was performed with pY1798 and known TC-markers, for example, hematopoietic-prostaglandin-D-synthase (HPGDS), or doublecortin-like kinase 1 (DCLK1)...
June 2017: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Pradipta Ghosh, Padmini Rangamani, Irina Kufareva
The canonical process of activation of heterotrimeric G proteins by G protein coupled receptors (GPCRs) is well studied. Recently, a rapidly emerging paradigm has revealed the existence of a new, non-canonical set of cytosolic G protein modulators, guanine exchange modulators (GEMs). Among G proteins regulators, GEMs are uniquely capable of initiating pleiotropic signals: these bifunctional modulators can activate cAMP inhibitory (Gi) proteins and inhibit cAMP-stimulatory (Gs) proteins through a single short evolutionarily conserved module...
April 3, 2017: Cell Cycle
A Natsume, T Kato, S Kinjo, A Enomoto, H Toda, S Shimato, F Ohka, K Motomura, Y Kondo, T Miyata, M Takahashi, T Wakabayashi
No abstract text is available yet for this article.
February 20, 2017: Oncogene
Pradipta Ghosh
Loss of cell polarity impairs organ development and function; it can also serve as one of the first triggers for oncogenesis. In 2006-2007 two groups simultaneously reported the existence of a special pathway for maintaining epithelial polarity in the face of environmental stressors. In this pathway, AMPK, a key sensor of metabolic stress stabilizes tight junctions, preserves cell polarity, and thereby, maintains epithelial barrier functions. Accumulating evidence since has shown that pharmacologic activation of AMPK by Metformin protects the epithelial barrier against multiple environmental and pathological stressful states and suppresses tumorigenesis...
February 15, 2017: Aging
Yang Ke, Tianhao Bao, Xuesong Wu, Haoran Tang, Yan Wang, Jiayun Ge, Bimang Fu, Xu Meng, Li Chen, Cheng Zhang, Yuqi Tan, Haotian Chen, Zhitang Guo, Fan Ni, Xuefen Lei, Zhitian Shi, Dong Wei, Lin Wang
Scutellarin is an active flavone from Erigeron breviscapine (vant) Hand Mass. This study aimed to investigate the potential role of scutellarin in migration and invasion of human hepatocellular carcinoma (HCC) cells and its possible mechanism. In comparison with the vehicle-treated controls, treatment with scutellarin (50 mg/kg/day) for 35 days significantly mitigated the lung and intrahepatic metastasis of HCC tumors in vivo. Scutellarin treatment significantly reduced HepG2 cell viability in a dose-dependent manner, and inhibited migration and invasion of HCC cells in vitro...
January 29, 2017: Biochemical and Biophysical Research Communications
Pradipta Ghosh, Nicolas Aznar, Lee Swanson, I-Chung Lo, Inmaculada Lopez-Sanchez, Jason Ear, Cristina Rohena, Nicholas Kalogriopoulos, Linda Joosen, Ying Dunkel, Nina Sun, Peter Nguyen, Deepali Bhandari
Canonical signal transduction via heterotrimeric G proteins is spatiotemporally restricted, i.e., triggered exclusively at the plasma membrane, only by agonist activation of G protein-coupled receptors via a finite process that is terminated within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a noncanonical pathway for activation of heterotrimeric G proteins via the nonreceptor guanidine-nucleotide exchange factor, GIV/Girdin. Biochemical, biophysical, and functional studies evaluating this pathway have unraveled its unique properties and distinctive spatiotemporal features...
December 7, 2016: Current Protocols in Chemical Biology
Kshitij Parag-Sharma, Anthony Leyme, Vincent DiGiacomo, Arthur Marivin, Stefan Broselid, Mikel Garcia-Marcos
GIV (aka Girdin) is a guanine nucleotide exchange factor that activates heterotrimeric G protein signaling downstream of RTKs and integrins, thereby serving as a platform for signaling cascade cross-talk. GIV is recruited to the cytoplasmic tail of receptors upon stimulation, but the mechanism of activation of its G protein regulatory function is not well understood. Here we used assays in humanized yeast models and G protein activity biosensors in mammalian cells to investigate the role of GIV subcellular compartmentalization in regulating its ability to promote G protein signaling...
December 30, 2016: Journal of Biological Chemistry
Nicolas Aznar, Arjun Patel, Cristina C Rohena, Ying Dunkel, Linda P Joosen, Vanessa Taupin, Irina Kufareva, Marilyn G Farquhar, Pradipta Ghosh
Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress...
November 4, 2016: ELife
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...
December 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...
November 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, Xiao-Yi 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...
November 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
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