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Fa-Min Zeng, Yang-Min Xie, Lian-Di Liao, Li-Yan Li, Bo Chen, Jian-Jun Xie, Li-Yan Xu, En-Min Li
The key molecular events that contribute to tumorigenesis are incompletely understood. The aim of the present study was to characterize and compare the biological phenotypes of three human telomerase reverse transcriptase (hTERT) and/or human papillomavirus 16 E6 and E7‑immortalized esophageal epithelial cell lines, NE2‑hTERT (NE2), NE3‑E6E7‑hTERT (NE3) and NEcA6‑E6E7‑hTERT (NEcA6). The present study used soft‑agar colony formation assays, tumorigenicity assays in nude mice, and cell proliferation, adhesion and migration assays to identify the biological characteristics of NE2, NE3 and NEcA6 cells...
October 6, 2016: Molecular Medicine Reports
Lihua Qi, Yu Yu, Xiaochun Chi, Danyu Lu, Yao Song, Youyi Zhang, Hongquan Zhang
Kindlin-2, a member of the Kindlin family focal adhesion proteins, plays an important role in cardiac development. It is known that defects in the Z-disc proteins lead to hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Our previous investigation showed that Kindlin-2 is mainly localized at the Z-disc and depletion of Kindlin-2 disrupts the structure of the Z-Disc. Here, we reported that depletion of Kindlin-2 leads to the disordered myocardial fibers, fractured and vacuolar degeneration in myocardial fibers...
September 20, 2016: Science China. Life Sciences
Yunwei Ou, Zitong Zhao, Weimin Zhang, Qingnan Wu, Chuanyue Wu, Xuefeng Liu, Ming Fu, Nan Ji, Dan Wang, Jiaji Qiu, Liwei Zhang, Chunjiang Yu, Yongmei Song, Qimin Zhan
Kindlin-2 promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. However, the role of Kindlin-2 in glioma has not been elucidated. We investigated Kindlin-2 expression in 188 human glioma tissue samples. High Kindlin-2 expression was correlated with high pathological grade and a worse prognosis. Kindlin-2 promoted glioma cell motility and proliferation both in vitro and in vivo. Importantly, Kindlin-2 activated the EGFR pathway and increased EGFR mRNA levels. In addition to up-regulating Y-box binding protein-1 (YB-1) and β-catenin expression, Kindlin-2 formed a transcriptional complex with YB-1 and β-catenin that bound to the EGFR promoter and enhanced transcription...
October 4, 2016: Oncotarget
Zhiyuan Zhang, Yongxin Mu, Jennifer Veevers, Angela K Peter, Ana Maria Manso, William H Bradford, Nancy D Dalton, Kirk L Peterson, Kirk U Knowlton, Robert S Ross, Xinmin Zhou, Ju Chen
BACKGROUND: The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation...
August 2016: Circulation. Heart Failure
Edward F Plow, Mitali Das, Katarzyna Bialkowska, Khalid Sossey-Alaoui
Kindlins are 4.1-ezrin-ridixin-moesin (FERM) domain containing proteins. There are three kindlins in mammals, which share high sequence identity. Kindlin-1 is expressed primarily in epithelial cells, kindlin-2 is widely distributed and is particularly abundant in adherent cells, and kindlin-3 is expressed primarily in hematopoietic cells. These distributions are not exclusive; some cells express multiple kindlins, and transformed cells often exhibit aberrant expression, both in the isoforms and the levels of kindlins...
April 2016: Discoveries
Meisi Yan, Lei Zhang, Yiqi Wu, Lei Gao, Weiwei Yang, Jing Li, Yubing Chen, Xiaoming Jin
Kindlin-2 is involved in activating the integrin signaling pathway which plays an important role in regulating cancer cell invasion. However, the role of kindlin-2 may vary among cancer types. The aim of this study was to explore the possible association between kindlin-2 and clear cell renal cell carcinoma (ccRCC), and its potential role in the prognosis of ccRCC. Immunohistochemistry assays were used to examine kindlin-2 expression levels in cancer tissues obtained from 336 patients with ccRCC. The correlation between kindlin-2 expression levels and pathologic variables was then analyzed...
July 2016: FEBS Open Bio
Maria Salmela, Pekka Rappu, Johanna Lilja, Henri Niskanen, Elina Taipalus, Johanna Jokinen, Jyrki Heino
Phorbol diester PMA (phorbol 12-myristate 13-acetate) is a well-known promoter of tumor progression. PMA also regulates cell adhesion by several mechanisms including conformational activation of integrins and integrin clustering. Here, PMA was shown to induce lamellipodia formation and reorganization of the adhesion sites as well as actin and vimentin filaments independently of integrin preactivation. To further analyze the mechanism of PMA action, the protein composition in the α1β1 integrin/collagen IV adhesion sites was analyzed by mass spectrometry and proteomics...
September 2016: International Journal of Biochemistry & Cell Biology
Jing-Ming Dong, Felicia Pei-Ling Tay, Hannah Lee-Foon Swa, Jayantha Gunaratne, Thomas Leung, Brian Burke, Ed Manser
Focal adhesions are protein complexes that link metazoan cells to the extracellular matrix through the integrin family of transmembrane proteins. Integrins recruit many proteins to these complexes, referred to as the "adhesome." We used proximity-dependent biotinylation (BioID) in U2OS osteosarcoma cells to label proteins within 15 to 25 nm of paxillin, a cytoplasmic focal adhesion protein, and kindlin-2, which directly binds β integrins. Using mass spectrometry analysis of the biotinylated proteins, we identified 27 known adhesome proteins and 8 previously unknown components close to paxillin...
2016: Science Signaling
Kamila Bledzka, Katarzyna Bialkowska, Khalid Sossey-Alaoui, Julia Vaynberg, Elzbieta Pluskota, Jun Qin, Edward F Plow
Reduced levels of kindlin-2 (K2) in endothelial cells derived from K2(+/-)mice or C2C12 myoblastoid cells treated with K2 siRNA showed disorganization of their actin cytoskeleton and decreased spreading. These marked changes led us to examine direct binding between K2 and actin. Purified K2 interacts with F-actin in cosedimentation and surface plasmon resonance analyses and induces actin aggregation. We further find that the F0 domain of K2 binds actin. A mutation, LK(47)/AA, within a predicted actin binding site (ABS) of F0 diminishes its interaction with actin by approximately fivefold...
April 11, 2016: Journal of Cell Biology
Chuanyue Wu, Jin You, Jijun Fu, Xingshun Wang, Yandong Zhang
RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription...
May 15, 2016: Molecular and Cellular Biology
Marina Theodosiou, Moritz Widmaier, Ralph T Böttcher, Emanuel Rognoni, Maik Veelders, Mitasha Bharadwaj, Armin Lambacher, Katharina Austen, Daniel J Müller, Roy Zent, Reinhard Fässler
Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate β1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn(2+). Despite compromised integrin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate spreading on FN...
2016: ELife
Xiaolin Wu, Wenwei Liu, Hong Jiang, Jing Chen, Jichun Wang, Rui Zhu, Bin Li
It is known that vascular smooth muscle cell (VSMC) proliferation and migration leads to intimal hyperplasia in cases of atherosclerosis and restenosis. In the present study, we investigated the effects of kindlin-2 on VSMC proliferation, migration and intimal hyperplasia, and the underlying mechanisms. The left common carotid artery of Sprague‑Dawley rats were subjected to balloon injury in order to induce intimal hyperplasia, and then transfected with kindlin-2 small interfering RNA (siRNA) lentivirus or negative control siRNA lentivirus...
February 2016: International Journal of Molecular Medicine
Jia-rong Yang, Tie-jun Pan, Hui Yang, Tao Wang, Wei Liu, Bo Liu, Wei-hong Qian
Invasive progression is the major lethal cause of prostate cancer. In this study, we aimed to investigate the role of kindlin-2, an integrin-binding focal adhesion protein, in the regulation of invasiveness of prostate cancer. We found that downregulation of kindlin-2 using small interfering RNA (siRNA) technology significantly inhibited the invasion of PC-3 and DU-145 prostate cancer cells in a Matrigel Transwell assay. Conversely, overexpression of kindlin-2 promoted the invasiveness of prostate cancer cells...
January 15, 2016: Gene
Sandrine Fiorucci, Xiaochen Lin, Karin Sadoul, Guy Fournet, Daniel Bouvard, Olga Vinogradova, Benoît Joseph, Marc R Block
We previously reported the anti-migratory function of 3-aryl-2-quinolone derivatives, chemically close to flavonoids (Joseph et al., 2002). Herein we show that 3-arylquinoline or 3-aryl-2-quinolone derivatives disrupt cell adhesion in a dose dependent and reversible manner yet antagonized by artificial integrin activation such as manganese. Relying on this anti-adhesive activity, a Structure-Activity Relationship (SAR) study was established on 20 different compounds to throw the bases of future optimization strategies...
2015: PloS One
Khalid Sossey-Alaoui, Edward F Plow
UNLABELLED: Prostate cancer is the second leading cause of cancer-related death in men, second only to lung cancer, mainly due to disease reoccurrence as a result to lack of response to androgen deprivation therapies (ADT) after castration. Patients with metastatic castration-resistant prostate cancer (mCRPC) have very limited treatment options, with docetaxel as the first-line standard of care, for which resistance to this chemotherapeutic ultimately develops. Therefore, finding ways to sensitize tumors to chemotherapies and to limit chemoresistance provides a viable strategy to extend the survival of mCRPC patients...
February 2016: Molecular Cancer Research: MCR
Hai-Feng Zhang, Abdulraheem Alshareef, Chengsheng Wu, Shang Li, Ji-Wei Jiao, Hui-Hui Cao, Raymond Lai, Li-Yan Xu, En-Min Li
Our previous studies have shown that loss of miR-200b enhances the invasiveness of esophageal squamous cell carcinoma (ESCC) cells. However, whether the miR-200-ZEB1/2-E-cadherin regulatory cascade, a master regulator of epithelial-to-mesenchymal transition (EMT), is involved in the regulation of ESCC invasion remains elusive. Here, we show that miR-200b represses ESCC cell invasion in vivo without altering the expression of E-cadherin and vimentin, two surrogate markers of EMT. However, an inverse correlation was observed between the expression levels of miR-200b and ZEB1/2 in both ESCC cell lines (n = 7, P < 0...
October 6, 2015: Oncotarget
Niku Oksala, Jenita Pärssinen, Ilkka Seppälä, Norman Klopp, Thomas Illig, Reijo Laaksonen, Mari Levula, Emma Raitoharju, Ivana Kholova, Thanos Sioris, Mika Kähönen, Terho Lehtimäki, Vesa P Hytönen
BACKGROUND: Kindlins (FERMT) are cytoplasmic proteins required for integrin (ITG) activation, leukocyte transmigration, platelet aggregation and thrombosis. Characterization of kindlins and their association with atherosclerotic plaques in human(s) is lacking. METHODS AND RESULTS: Exploratory microarray (MA) was first performed followed by selective quantitative validation of robustly expressed genes with qRT-PCR low-density array (LDA). In LDA, ITGA1 (1.30-fold, p = 0...
September 2015: Atherosclerosis
Chuanyue Wu, Hongli Jiao, Yumei Lai, Wei Zheng, Ka Chen, Hong Qu, Weimin Deng, Pingping Song, Ke Zhu, Huiling Cao, Deborah L Galson, Jie Fan, Hee-Jeong Im, Yujie Liu, Ju Chen, Di Chen, Guozhi Xiao
The signals that control skeletogenesis are incompletely understood. Here we show that deleting Kindlin-2 in Prx1-expressing mesenchymal progenitors in mice causes neonatal lethality, chondrodysplasia and loss of the skull vault. Kindlin-2 ablation reduces chondrocyte density by decreasing cell proliferation and increasing apoptosis, and disrupts column formation, thus impairing the formation of the primary ossification center and causing severe limb shortening. Remarkably, Kindlin-2 localizes to not only focal adhesions, but also to the nuclei of chondrocytes...
2015: Nature Communications
Lihua Qi, Yu Yu, Xiaochun Chi, Weizhi Xu, Danyu Lu, Yao Song, Youyi Zhang, Hongquan Zhang
Kindlin-2, as an integrin-interacting protein, was known to be required for the maintenance of cardiac structure and function in zebrafish. However, the mechanism remains unclear. We found that Kindlin-2 interacts and colocalizes with α-actinin-2 at the Z-disc of mouse cardiac muscles and there Kindlin-2 also interacts with β1 integrin. Knockdown of Kindlin-2 influences the association of β1 integrin with α-actinin-2 and disrupts the structure of the Z-disc and leads to cardiac dysfunction. Our data indicated that Kindlin-2 is a novel α-actinin-2-interacting protein and plays an important role in the regulation of cardiac structure and function...
July 22, 2015: FEBS Letters
Ji-Chun Yang, Xiao-Feng Shi, Jian-Song Huang, Zhang-Biao Long, Bing Xiao, Zheng Ruan, Xiao-Dong Xi
UNLABELLED: OBJLECTIVE: To investigate the effect of integrin β3 cytoplasmic NITY motif on αIIbβ3-mediated cell functions. METHODS: Stable Chinese hamster ovary (CHO) cell lines that co-express human wild type integrin αIIb and wild type β3 or mutant β3ΔNITY (β3 deleting cytoplasmic NITY motif) were established. Expression of αIIb and β3 were tested by Western blot and flow cytometry in CHO cell lines. Spreading and adhesion of stable cell lines on immobilized fibrinogen were examined...
June 2015: Zhongguo Shi Yan Xue Ye Xue za Zhi
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