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Elmer Hoekstra, Asha M Das, Marcella Willemsen, Marloes Swets, Peter J K Kuppen, Christien J van der Woude, Marco J Bruno, Jigisha P Shah, Timo L M Ten Hagen, John D Chisholm, William G Kerr, Maikel P Peppelenbosch, Gwenny M Fuhler
Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene...
September 28, 2016: Oncotarget
Anaïs Fradet, Jamie Fitzgerald
The INPPL1 (inositol polyphosphate phosphatase-like 1) gene encodes the inositol phosphatase, SHIP2 (for src homology 2 domain-containing inositol phosphatase 2). SHIP2 functions to dephosphorylate, and negatively regulate, the lipid second messenger phosphatidylinositol (3,4,5)P3. SHIP2 has been well studied in the area of insulin resistance and obesity but has roles in cancer and other disorders. Recently, it was reported that mutations in INPPL1 cause opsismodysplasia, a rare, autosomal recessive severe skeletal dysplasia...
October 6, 2016: Journal of Human Genetics
Charles V Rajadurai, Serhiy Havrylov, Paula P Coelho, Colin D H Ratcliffe, Kossay Zaoui, Bruce H Huang, Anie Monast, Naila Chughtai, Veena Sangwan, Frank B Gertler, Peter M Siegel, Morag Park
Invadopodia are specialized membrane protrusions that support degradation of extracellular matrix (ECM) by cancer cells, allowing invasion and metastatic spread. Although early stages of invadopodia assembly have been elucidated, little is known about maturation of invadopodia into structures competent for ECM proteolysis. The localized conversion of phosphatidylinositol(3,4,5)-triphosphate and accumulation of phosphatidylinositol(3,4)-bisphosphate at invadopodia is a key determinant for invadopodia maturation...
September 12, 2016: Journal of Cell Biology
William's Elong Edimo, Ana Raquel Ramos, Somadri Ghosh, Jean-Marie Vanderwinden, Christophe Erneux
The phosphoinositide 5-phosphatases consist of several enzymes that have been shown to modulate cell migration and invasion. SHIP2, one family member, is known to interact with growth factor receptors and cytoskeletal proteins. In a human model of glioblastoma 1321 N1 cells, we recently identified Myo1c as a new interactor of SHIP2. This was shown in a complex of proteins also containing filamin A. We show here that SHIP2 localization at lamellipodia and ruffles is impaired in Myo1c depleted cells. In the absence of Myo1c, N1 cells tend to associate to form clusters...
August 5, 2016: Biochemical and Biophysical Research Communications
Cori Feist, Paul Holden, Jamie Fitzgerald
This study aimed to identify the genetic basis of a severe skeletal lethal dysplasia. The main clinical features of two affected fetuses included short limbs with flared metaphyses, bowed radii, femora and tibiae, irregular ossification of hands and feet, and marked platyspondyly. Affected and nonaffected family members were subjected to whole-exome sequencing, followed by immunoblot analysis on amniocytes isolated from one of the affected individuals. Unique compound heterozygous variants in the inositol polyphosphate phosphatase-like 1 (INPPL1) gene encoding the SHIP2 protein were identified in both affected individuals...
October 2016: Clinical Dysmorphology
Johanne Le Coq, Luis Heredia Gallego, Daniel Lietha
The Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) catalyses the dephosphorylation of the phospholipid phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) to form PI(3,4)P2. PI(3,4,5)P3 is a key lipid second messenger, which can recruit signalling proteins to the plasma membrane and subsequently initiate numerous downstream signalling pathways responsible for the regulation of a plethora of cellular events such as proliferation, growth, apoptosis and cytoskeletal rearrangements. SHIP2 has been heavily implicated with several serious diseases such as cancer and type 2 diabetes but its regulation remains poorly understood...
June 2016: Protein Journal
Liqun Zhang, Susmita Borthakur, Matthias Buck
The process of protein complex dissociation remains to be understood at the atomic level of detail. Computers now allow microsecond timescale molecular-dynamics simulations, which make the visualization of such processes possible. Here, we investigated the dissociation process of the EphA2-SHIP2 SAM-SAM domain heterodimer complex using unrestrained all-atom molecular-dynamics simulations. Previous studies on this system have shown that alternate configurations are sampled, that their interconversion can be fast, and that the complex is dynamic by nature...
February 23, 2016: Biophysical Journal
Qian Yang, Yiqiong Ma, Yipeng Liu, Wei Liang, Xinghua Chen, Zhilong Ren, Huiming Wang, Pravin C Singhal, Guohua Ding
Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)-induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain-containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling...
January 1, 2016: Molecular Biology of the Cell
Sattar Gorgani-Firuzjaee, Reza Meshkani
Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM)...
December 2015: Free Radical Biology & Medicine
Shannon K Hughes, Madeleine J Oudin, Jenny Tadros, Jason Neil, Amanda Del Rosario, Brian A Joughin, Laila Ritsma, Jeff Wyckoff, Eliza Vasile, Robert Eddy, Ulrike Philippar, Alisha Lussiez, John S Condeelis, Jacco van Rheenen, Forest White, Douglas A Lauffenburger, Frank B Gertler
During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express Mena(INV), which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling...
November 1, 2015: Molecular Biology of the Cell
Yan Ye, Yan Mei Ge, Miao Miao Xiao, Li Mei Guo, Qun Li, Ji Qing Hao, Jie Da, Wang Lai Hu, Xu Dong Zhang, Jiegou Xu, Lin Jie Zhang
BACKGROUND: The Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is implicated in diabetes, arthrosclerosis, and cancer. However, the role of SHIP2 in human gastric cancer remains unclear. METHODS: The expression levels of SHIP2 in gastric cancer tissues, a panel of gastric cancer cell lines, and normal gastric epithelial cells were analyzed by immunohistochemistry (IHC), Western blot, and real-time quantitative RT-PCR (qRT-PCR). Gastric cancer cells with either overexpressed SHIP2 or co-overexpressed SHIP2 and Akt were analyzed to determine cell proliferation, colony formation, apoptosis, cell migration, and invasion assays...
March 2016: Journal of Gastroenterology
Sattar Gorgani-Firuzjaee, Shohreh Khatami, Khosrow Adeli, Reza Meshkani
Hepatic de-novo lipogenesis and production of triglyceride rich VLDL are regulated via the phosphoinositide 3-kinase cascade, however, the role of a negative regulator of this pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we investigated the molecular link between SHIP2 expression and metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells. The results showed that overexpression of the wild type SHIP2 gene (SHIP2-WT) led to a higher total lipid content (28%) compared to control, whereas overexpression of the dominant negative SHIP2 gene (SHIP2-DN) reduced total lipid content in oleate treated cells by 40%...
September 4, 2015: Biochemical and Biophysical Research Communications
Sattar Gorgani-Firuzjaee, Khosrow Adeli, Reza Meshkani
The serine-threonine kinase Akt regulates proliferation and survival by phosphorylating a network of protein substrates; however, the role of a negative regulator of the Akt pathway, the SH2-domain-containing inositol 5-phosphatase (SHIP2) in apoptosis of the hepatocytes, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to apoptosis using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to palmitate (0.5 mM). Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) significantly reduced palmitate-induced apoptosis in HepG2 cells, as these cells had increased cell viability, decreased apoptotic cell death and reduced the activity of caspase-3, cytochrome c and poly (ADP-ribose) polymerase...
August 21, 2015: Biochemical and Biophysical Research Communications
Qingjuan Liu, Ruiying Wang, Hong Zhou, Lihui Zhang, Yanping Cao, Xianjuan Wang, Yongmei Hao
This study is to investigate the influence of SHIP2 on palmitic acid stimulated islet β cell and insulin secretion, as well as its role in pI3K/Akt pathway. We defined four groups: control, acid group, acid + NC siRNA group and acid + siRNA transfection group. The control was neither treated by palmitic acid nor transfection. The acid group was subjected to palmitic acid incubation. The acid + NC siRNA group was transiently transfected by NC siRNA, then was stimulated by palmitic acid. The acid + siRNA group was transiently transfected by siRNA, then was stimulated by palmitic acid...
2015: International Journal of Clinical and Experimental Medicine
Y-M Hao, Q-J Liu, R-Y Wang, Y-P Cao, Y Zhang, L-F Zuo
OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance in the target tissue of insulin with insufficient insulin secretion in pancreatic β-cells. Src homology 2-containing 5'-inositol phosphatase 2 (SHIP2) is a lipid phosphatase that hydrolyzes PI3-kinase product PI(3,4,5)P3 to PI(3,4)P2, which contributes to the negative regulation of insulin signaling both in vitro and in vivo. Some polymorphisms of SHIP2 have been reported to be associated with the metabolic syndrome including T2DM and hypertension in British, French and Japanese T2DM population...
January 2015: European Review for Medical and Pharmacological Sciences
Ju Yang, Maoying Fu, Yaoguang Ding, Yajing Weng, Weifei Fan, Xiaolin Pu, Zhijun Ge, Feng Zhan, Huihui Ni, Wei Zhang, Feng Jin, Ning Xu, Jiang Li, Liang Qiu, Jun Wang, Xuefeng Gu
SH2-containing inositol 5'-phosphatase 2 (SHIP2), which generally regulates insulin signaling, cytoskeleton remodeling, and receptor endocytosis, has been suggested to play a significant role in tumor development and progression. However, the associations between SHIP2 expression and the clinical features to evaluate its clinicopathologic significance in colorectal cancer (CRC) have not been determined yet. In the present study, one-step quantitative real-time polymerase chain reaction (qPCR) test and immunohistochemistry (IHC) analysis with CRC tissue microarrays (TMA) were employed to evaluate the mRNA and protein expression of SHIP2 in CRC...
2014: Disease Markers
Emmanuel Boucrot, Antonio P A Ferreira, Leonardo Almeida-Souza, Sylvain Debard, Yvonne Vallis, Gillian Howard, Laetitia Bertot, Nathalie Sauvonnet, Harvey T McMahon
Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition...
January 22, 2015: Nature
Germaine D Agollah, Manuel L Gonzalez-Garay, John C Rasmussen, I-Chih Tan, Melissa B Aldrich, Chinmay Darne, Caroline E Fife, Renie Guilliod, Erik A Maus, Philip D King, Eva M Sevick-Muraca
The lymphatic vasculature plays a critical role in a number of disease conditions of increasing prevalence, such as autoimmune disorders, obesity, blood vascular diseases, and cancer metastases. Yet, unlike the blood vasculature, the tools available to interrogate the molecular basis of lymphatic dysfunction/disease have been lacking. More recently, investigators have reported that dysregulation of the PI3K pathway is involved in syndromic human diseases that involve abnormal lymphatic vasculatures, but there have been few compelling results that show the direct association of this molecular pathway with lymphatic dysfunction in humans...
2014: PloS One
Srishti Kotiyal, Susinjan Bhattacharya
A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo "epithelial to mesenchymal transition" (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation...
October 10, 2014: Biochemical and Biophysical Research Communications
Frank Wang, Sylvia Cheung, Alice Mui
No abstract text is available yet for this article.
November 2014: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
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