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Tzu-Pin Shentu, Ming He, Xiaoli Sun, Jianlin Zhang, Fan Zhang, Brendan Gongol, Traci L Marin, Jiao Zhang, Liang Wen, Yinsheng Wang, Gregory G Geary, Yi Zhu, David A Johnson, John Y-J Shyy
OBJECTIVE: Cortactin translocates to the cell periphery in vascular endothelial cells (ECs) on cortical-actin assembly in response to pulsatile shear stress. Because cortactin has putative sites for AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) deacetylation, we examined the hypothesis that AMPK and SIRT1 coregulate cortactin dynamics in response to shear stress. APPROACH AND RESULTS: Analysis of the ability of AMPK to phosphorylate recombinant cortactin and oligopeptides whose sequences matched AMPK consensus sequences in cortactin pointed to Thr-401 as the site of AMPK phosphorylation...
October 6, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Shuhei Nakamura, Junya Hasegawa, Tamotsu Yoshimori
Macroautophagy (autophagy) is a multistep intracellular degradation system. Autophagosomes form, mature, and ultimately fuse with lysosomes, where their sequestered cargo molecules are digested. In contrast to autophagosome formation, our knowledge of autophagosome-lysosome fusion is limited. In a recent study, we identified a novel regulator of autophagy, INPP5E (inositol polyphosphate-5-phosphatase E), which is essential for autophagosome-lysosome fusion. INPP5E primarily functions in neuronal cells, and knockdown of the corresponding gene causes accumulation of autophagosomes by impairing fusion with lysosomes...
October 7, 2016: Autophagy
Huo Wu, Xiaoqian Jing, Xi Cheng, Yonggang He, Lei Hu, Haoxuan Wu, Feng Ye, Ren Zhao
Asporin has been implicated as an oncogene in various types of human cancers; however, the roles of asporin in the development and progression of colorectal cancer (CRC) have not yet been determined. With clinical samples, we found that asporin was highly expressed in CRC tissues compared to adjacent normal tissues and the asporin expression levels were significantly associated with lymph node metastasis status and TNM stage of the patients. Through knockdown of asporin in CRC cell lines RKO and SW620 or overexpression of asporin in cell lines HT-29 and LoVo, we found that asporin could enhance wound healing, migration and invasion abilities of the CRC cells...
September 29, 2016: Oncotarget
Pirjo Spuul, Thomas Daubon, Bettina Pitter, Florian Alonso, Isabelle Fremaux, IJsbrand Kramer, Eloi Montanez, Elisabeth Génot
During angiogenic sprouting, endothelial tip cells emerge from existing vessels in a process that requires vascular basement membrane degradation. Here, we show that F-actin/cortactin/P-Src-based matrix-degrading microdomains called podosomes contribute to this step. In vitro, VEGF-A/Notch signaling regulates the formation of functional podosomes in endothelial cells. Using a retinal neovascularization model, we demonstrate that tip cells assemble podosomes during physiological angiogenesis in vivo. In the retina, podosomes are also part of an interconnected network that surrounds large microvessels and impinges on the underlying basement membrane...
October 4, 2016: Cell Reports
Xinyong Tian, Tomomi Ohmura, Alok S Shah, Sophia Son, Yufeng Tian, Anna A Birukova
Rapid changes in microtubule (MT) polymerization dynamics affect regional activity of small GTPases RhoA and Rac1, which play a key role in the regulation of actin cytoskeleton and endothelial cell (EC) permeability. This study tested the role of End Binding Protein-1 (EB1) in the mechanisms of increased and decreased EC permeability caused by thrombin and hepatocyte growth factor (HGF) and mediated by RhoA and Rac1 GTPases, respectively. Stimulation of human lung EC with thrombin inhibited peripheral MT growth, which was monitored by morphological and biochemical evaluation of peripheral MT and the levels of stabilized MT...
September 23, 2016: Cellular Signalling
Fabien Binamé, Aurélien Bidaud-Meynard, Laure Magnan, Léo Piquet, Bertille Montibus, Anne Chabadel, Frédéric Saltel, Valérie Lagrée, Violaine Moreau
Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges...
September 26, 2016: Journal of Cell Biology
Xiaoqian Jing, Huo Wu, Xiaopin Ji, Haoxuan Wu, Minmin Shi, Ren Zhao
Cortactin (CTTN), a major substrate of the Src tyrosine kinase, has been implicated in cell proliferation, motility and invasion in various types of cancer. However, the molecular mechanisms of CTTN-driven malignant behavior remain unclear. In the current study, we determined the expression of CTTN in colorectal cancer and investigated its underlying mechanism in the metastasis of colorectal cancer. We confirmed increased CTTN expression in lymph node-positive CRC specimens and highly invasive CRC cell lines...
August 31, 2016: Oncology Reports
Olivia Muriel, Alejandra Tomas, Cameron C Scott, Jean Gruenberg
We have used in vivo and in vitro strategies to study the mechanisms of multivesicular endosomes biogenesis. We found that, while annexinA2 and Arp2/3 mediate F-actin nucleation and branching, respectively, the ERM protein moesin supports the formation of F-actin networks on early endosomes. We also found that moesin plays no role during endocytosis and recycling to the plasma membrane, but is absolutely required, much like actin, for early-to-late endosome transport and multivesicular endosome formation. Both actin network formation in vitro and early-to-late endosome transport in vivo also depend on the F-actin binding protein cortactin...
September 7, 2016: Molecular Biology of the Cell
Rachel J Watkins, Waraporn Imruetaicharoenchoke, Martin L Read, Neil Sharma, Vikki L Poole, Erica Gentillin, Sukhchain Bansal, Emy Bosseboeuf, Rachel Fletcher, Hannah R Nieto, Ujjal Mallick, Allan Hackshaw, Hisham Mehanna, Kristien Boelaert, Vicki E Smith, Christopher J McCabe
CONTEXT: Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. OBJECTIVE: The proto-oncogene PTTG1-Binding Factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumour aggressiveness. This study aimed to understand the role of PBF in tumour cell invasion and identify possible routes to inhibit its action. Design, Setting, Patients, and Interventions: Thyroid, breast and colorectal cells were transfected with PBF and cultured for in vitro analysis...
September 7, 2016: Journal of Clinical Endocrinology and Metabolism
Hiroshi Yamada, Tetsuya Takeda, Hiroyuki Michiue, Tadashi Abe, Kohji Takei
The endocytic protein dynamin participates in the formation of actin-based membrane protrusions such as podosomes, pseudopodia, and invadopodia, which facilitate cancer cell migration, invasion, and metastasis. However, the role of dynamin in the formation of actin-based membrane protrusions at the leading edge of cancer cells is unclear. In this study, we demonstrate that the ubiquitously expressed dynamin 2 isoform facilitates cell migration by stabilizing F-actin bundles in filopodia of the lung cancer cell line H1299...
September 2016: International Journal of Oncology
Yufeng Tian, Xinyong Tian, Grzegorz Gawlak, Nicolene Sarich, David B Sacks, Anna A Birukova, Konstantin G Birukov
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) attenuates agonist-induced endothelial cell (EC) permeability and increases pulmonary endothelial barrier function via enhancement of both the peripheral actin cytoskeleton and cell junctions mediated by Rac1 and Cdc42 GTPases. This study evaluated the role for the multifunctional Rac1/Cdc42 effector and regulator, IQGAP1, as a molecular transducer of the OxPAPC-mediated EC barrier enhancing signal. IQGAP1 knockdown in endothelial cells by gene-specific siRNA abolished OxPAPC-induced enlargement of VE-cadherin-positive adherens junctions, suppressed peripheral accumulation of actin polymerization regulators, namely cortactin, N-WASP and Arp3, and attenuated remodeling of the peripheral actin cytoskeleton...
August 26, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
André Luis Ribeiro Ribeiro, Natacha Malu Miranda da Costa, Adriane Sousa de Siqueira, Walessa Brasil da Silva, Maria Sueli da Silva Kataoka, Ruy Gastaldoni Jaeger, Sérgio de Melo Alves-Junior, Andrew M Smith, João de Jesus Viana Pinheiro
OBJECTIVE: Keratocystic odontogenic tumor (KOT) is an odontogenic neoplasm that shows aggressive clinical behavior and local invasiveness. Invadopodia are actin-rich cellular protrusions exhibiting proteolytic pericellular activity, thereby inducing focal invasion in neoplastic cells and increasing neoplasms aggressiveness. Thus, this study aimed to evaluate immunoexpression of invadopodia-related proteins, cortactin, MT1-MMP, Tks4, and Tks5, in KOT. STUDY DESIGN: Immunohistochemistry of 16 cases of KOT, eight cases of calcifying cystic odontogenic tumor (CCOT), and eight samples of the oral mucosa (OM) was carried out to assess the expression of the above described invadopodia-related proteins in the basal and suprabasal layer...
October 2016: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Da-Yuan Chen, Matloob Husain
Influenza A virus (IAV) is well-known to exploit host factors to its advantage. Here, we report that IAV exploits host cortactin, an actin filament-stabilising protein for infection in epithelial cells. By using RNA interference-mediated knockdown and overexpression approach, we demonstrate that cortactin promotes IAV infection. However, cortactin polypeptide undergoes the degradation during late IAV infection. By perturbing the lysosome and proteasome, two main compartments governing the degradation of mammalian proteins, we demonstrate that a lysosome-associated apoptotic pathway mediates the degradation of cortactin in IAV-infected cells...
October 2016: Virology
Gregory Adams, Jiajia Zhou, Wenwen Wang, Huihui Wu, Jie Quan, Yingying Liu, Peng Xia, Zhikai Wang, Shu Zhou, Jiying Jiang, Fei Mo, Xiaoxuan Zhuang, Kelwyn Thomas, Donald L Hill, Felix O Aikhionbare, Ping He, Xing Liu, Xia Ding, Xuebiao Yao
Cell migration is orchestrated by dynamic interactions of microtubules with the plasma membrane cortex. How these interactions facilitate these dynamic processes is still being actively investigated. TIP150 is a newly characterized microtubule plus end tracking protein essential for mitosis and entosis (Ward, T., Wang, M., Liu, X., Wang, Z., Xia, P., Chu, Y., Wang, X., Liu, L., Jiang, K., Yu, H., Yan, M., Wang, J., Hill, D. L., Huang, Y., Zhu, T., and Yao, X. (2013) Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis...
September 23, 2016: Journal of Biological Chemistry
Lahiru Gangoda, Suresh Mathivanan
The role of cortactin, a regulator of late endosomal trafficking, in the biogenesis and secretion of exosomes is poorly understood. In this issue, Sinha et al. (2016. J. Cell Biol. elucidate the role of cortactin as a positive regulator of late endosomal docking and exosome secretion.
July 18, 2016: Journal of Cell Biology
Rajiv Sainath, Andrea Ketschek, Leah Grandi, Gianluca Gallo
Chondroitin sulfate proteoglycans (CSPGs) inhibit the formation of axon collateral branches. The regulation of the axonal cytoskeleton and mitochondria are important components of the mechanism of branching. Actin-dependent axonal plasticity, reflected in the dynamics of axonal actin patches and filopodia, is greatest along segments of the axon populated by mitochondria. We report that CSPGs partially depolarize the membrane potential of axonal mitochondria, which impairs the dynamics of the axonal actin cytoskeleton and decreases the formation and duration of axonal filopodia, the first steps in the mechanism of branching...
July 18, 2016: Developmental Neurobiology
Seema Sinha, Daisuke Hoshino, Nan Hyung Hong, Kellye C Kirkbride, Nathan E Grega-Larson, Motoharu Seiki, Matthew J Tyska, Alissa M Weaver
Exosomes are extracellular vesicles that influence cellular behavior and enhance cancer aggressiveness by carrying bioactive molecules. The mechanisms that regulate exosome secretion are poorly understood. Here, we show that the actin cytoskeletal regulatory protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in cancer cells leads to a respective decrease or increase in exosome secretion, without altering exosome cargo content. Live-cell imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular late endosomes (MVEs)...
July 18, 2016: Journal of Cell Biology
W-D Wu, M Wang, H-H Ding, Z-J Qiu
OBJECTIVE: The hemerythrin-like domain of F-box and leucine-rich repeat protein 5 (FBXL5), an E3 ubiquitin ligase subunit, has critical roles in the regulation of cancer cells metastasis and chemoresistance by targeting diverse substrates for ubiquitin-mediated destruction. MATERIALS AND METHODS: Here, we report that FBXL5 interacts with Rho GDP dissociation inhibitor 2 (RhoGDI2) and attenuates RhoGDI2-induced cisplatin resistance in gastric cancer cells. By utilizing immunoprecipitation (IP) coupled with mass spectrometry assay, we found that FBXL5 regulated gastric cancers migration via cortactin destruction...
June 2016: European Review for Medical and Pharmacological Sciences
Elena Cortés-Vicente, Eduard Gallardo, María Ángeles Martínez, Jordi Díaz-Manera, Luis Querol, Ricard Rojas-García, Isabel Illa
IMPORTANCE: Double-seronegative myasthenia gravis (dSNMG) includes patients with myasthenia gravis (MG) without detectable antibodies to the nicotinic acetylcholine receptor (AChR) or to muscle-specific tyrosine kinase (MuSK). The lack of a biomarker hinders the diagnosis and clinical management in these patients. Cortactin, a protein acting downstream from agrin/low-density lipoprotein receptor-related protein 4 (LRP4)/MuSK, has been described as an antigen in dSNMG. OBJECTIVE: To describe the frequency and clinical features of patients with dSNMG who have cortactin antibodies...
September 1, 2016: JAMA Neurology
Jagadeesh Janjanam, Gadiparthi N Rao
Monocyte chemotactic protein 1 (MCP1) stimulates phosphorylation of cortactin on Y421 and Y446 residues in a time-dependent manner and phosphorylation at Y446 but not Y421 residue is required for MCP1-induced CDK-interacting protein 1 (p21Cip1) nuclear export and degradation in facilitating human aortic smooth muscle cell (HASMC) proliferation. In addition, MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation are dependent on Fyn activation. Upstream to Fyn, MCP1 stimulated C-C chemokine receptor type 2 (CCR2) and Gi/o and inhibition of either one of these molecules using their specific antagonists or inhibitors attenuated MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation...
2016: Scientific Reports
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