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Src kinase

Binod Kumar, Dipanjan Dutta, Jawed Iqbal, Mairaj Ahmed Ansari, Arunava Roy, Leela Chikoti, Gina Pisano, Mohanan Valiya Veettil, Bala Chandran
Kaposi's sarcoma-associated herpesvirus (KSHV) binding to the endothelial cell surface heparan sulfate is followed by sequential interactions with α3β1, αVβ3 and αVβ5 integrins and Ephrin A2 receptor tyrosine kinase (EphA2R). These interactions activate host cell pre-existing FAK, Src, PI3-K and RhoGTPase signaling cascades, c-Cbl mediated ubiquitination of receptors, recruitment of CIB1, p130Cas and Crk adaptor molecules, and membrane bleb formation leading to lipid raft dependent macropinocytosis of KSHV into human microvascular dermal endothelial (HMVEC-d) cells...
October 2016: PLoS Pathogens
Yong-Chao Ma, Zhi-Xin Wang, Shao-Ju Jin, Yan-Xin Zhang, Guo-Qiang Hu, Dong-Tao Cui, Jiang-Shuan Wang, Min Wang, Fu-Qing Wang, Zhi-Jun Zhao
Both tyrosine kinase and topoisomerase II (TopII) are important anticancer targets, and their respective inhibitors are widely used in cancer therapy. However, some combinations of anticancer drugs could exhibit mutually antagonistic actions and drug resistance, which further limit their therapeutic efficacy. Here, we report that HMNE3, a novel bis-fluoroquinolone chalcone-like derivative that targets both tyrosine kinase and TopII, induces tumor cell proliferation and growth inhibition. The viabilities of 6 different cancer cell lines treated with a range of HMNE3 doses were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay...
2016: PloS One
Jesus Duque-Afonso, Chiou-Hong Lin, Kyuho Han, Michael C Wei, Jue Feng, Jason Kurzer, Corina Schneidawind, Stephen H K Wong, Michael C Bassik, Michael L Cleary
There is limited understanding of how signaling pathways are altered by oncogenic fusion transcription factors that drive leukemogenesis. To address this, we interrogated activated signaling pathways in a comparative analysis of mouse and human leukemias expressing the fusion protein E2A-PBX1, which is present in 5-7% of pediatric and 50% of pre-B-cell receptor (preBCR+) acute lymphocytic leukemia (ALL). In this study, we describe remodeling of signaling networks by E2A-PBX1 in pre-B-ALL which result in hyperactivation of the key oncogenic effector enzyme PLCγ2...
October 7, 2016: Cancer Research
Yu Jin Kim, Sungyoul Hong, Minjung Sung, Min Jeong Park, Kyungsoo Jung, Ka-Won Noh, Doo-Yi Oh, Mi-Sook Lee, Ensel Oh, Young Kee Shin, Yoon-La Choi
Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC)...
October 14, 2016: Oncotarget
Susan R Mallery, Daren Wang, Brian Santiago, Ping Pei, Steven Schwendeman, Kari Nieto, Richard Spinney, Meng Tong, George Koutras, Byungdo B Han, Andrew S Holpuch, James C Lang
Over 1/3 of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers...
October 18, 2016: Cancer Prevention Research
Lin Liu, PeiYu Huang, ZhiHui Wang, Nan Chen, Con Tang, Zhong Lin, PeiJian Peng
BACKGROUND: Previous studies have reported that eEF-2 kinase is associated with tumour cell sensitivity to certain therapies. In the present study, we investigated the relationship between eEF-2 kinase and lapatinib, a dual inhibitor of EGFR and HER-2, in nasopharyngeal carcinoma (NPC) cells. METHODS: The effect of treatment on the growth and proliferation of NPC cells was measured by three methods: cell counting, crystal violet staining and colony counting. Apoptosis was evaluated by flow cytometry to determine Annexin V-APC/7-AAD and cleaved PARP levels, and the results were further confirmed by Western blot analysis...
October 19, 2016: BMC Cancer
Mihwa Kim, Ji-Yeon Jung, Seungho Choi, Hyunseung Lee, Liza D Morales, Jeong-Tae Koh, Sun Hun Kim, Yoo-Duk Choi, Chan Choi, Thomas J Slaga, Won Jae Kim, Dae Joon Kim
Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family receptor alpha 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy...
October 18, 2016: Autophagy
Estelle R Simo-Cheyou, George Vardatsikos, Ashok K Srivastava
We have previously demonstrated that the non-receptor protein tyrosine kinase (NR-PTK) c-Src is an upstream regulator of endothelin-1 (ET-1) and angiotensin II-induced activation of protein kinase B (PKB) signaling in vascular smooth muscle cells (VSMCs). We have also demonstrated that ET-1 potently induces the expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor that is overexpressed in models of vascular diseases, such as atherosclerosis. However, the involvement of c-Src in ET-1‑induced Egr-1 expression has not yet been investigated and its role in mitogen-activated protein kinase (MAPK) signaling remains controversial...
October 6, 2016: International Journal of Molecular Medicine
Mohammad Shahidullah, Amritlal Mandala, Nicholas A Delamere
Insulin has been shown to elicit changes of Na,K-ATPase activity in various tissues. Na,K-ATPase in the nonpigmented ciliary epithelium (NPE) plays a role in aqueous humor secretion and changes of Na,K-ATPase activity impact the driving force. Because we detect a change of NPE Na,K-ATPase activity in response to insulin, studies were carried out to examine the response mechanism. Ouabain-sensitive rubidium (Rb) uptake by cultured NPE cells, measured as a functional index of Na,K-ATPase-mediated inward potassium transport, was found to increase in cells exposed for 5 min to insulin...
October 17, 2016: Journal of Cellular Physiology
Ji-Eun Im, Sun-Hwa Song, Wonhee Suh
PURPOSE: Stem cell factor (SCF) has been recently acknowledged as a novel endothelial permeability factor. However, the mechanisms by which SCF-induced activation of the SCF cognate receptor, cKit, enhances endothelial permeability have not been fully elucidated. This study aimed to investigate the role of Src in SCF-induced breakdown of the blood-retinal barrier (BRB). METHODS: In vitro endothelial permeability and in vivo retinal vascular permeability assays were performed to investigate the role of Src in SCF-induced breakdown of the BRB...
2016: Molecular Vision
Tiantian Luo, Jing Hu, Dan Xi, Haowei Xiong, Wenshuai He, Jichen Liu, Menghao Li, Hao Lu, Jinzhen Zhao, Wenyan Lai, Zhigang Guo
Previously, we reported that heat shock protein (HSP)65 impairs the effects of high-density lipoprotein on macrophages. We also showed that immune response activation adversely affects reverse cholesterol transport (RCT). In this study, we investigated the effects of the Src family kinase lymphocyte-specific protein tyrosine kinase (Lck) and elucidated the mechanism underlying HSP65-regulated cholesterol efflux in T cells. We evaluated cell proliferation, Lck expression, and inflammatory cytokine production in Jurkat cells and CD4(+) T cells...
October 14, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Chun-Hui Zhang, Kai Chen, Yan Jiao, Lin-Li Li, Ya-Ping Li, Rong-Jie Zhang, Ming-Wu Zheng, Lei Zhong, Shen-Zhen Huang, Chun-Li Song, Wan-Ting Lin, Jiao Yang, Rong Xiang, Bing Peng, Jun-Hong Han, Guang-Wen Lu, Yu-Quan Wei, Sheng-Yong Yang
Herein we report the sophisticated process of structural optimization towards a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo, but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays, and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an)...
October 14, 2016: Journal of Medicinal Chemistry
Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee, Yung-Jue Bang, Seock-Ah Im
Purpose: KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo. Materials and Methods: The anti-tumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay...
October 6, 2016: Cancer Research and Treatment: Official Journal of Korean Cancer Association
Dominic J Pollard, Joanna C Young, Valentina Covarelli, Silvia Herrera-León, Thomas R Connor, Maria Fookes, Danielle Walker, Aurora Echeita, Nicholas R Thomson, Cedric N Berger, Gad Frankel
Salmonella spp. utilize type III secretion systems (T3SS) to translocate effectors into the cytosol of mammalian host cells, subverting cell signaling and facilitating the onset of gastroenteritis. In this study we compared a draft genome assembly of S. enterica subsp. salamae strain 3588/07 (S. salamae) against the genomes of S. enterica subsp. enterica serovar Typhimurium strain LT2 and S. bongori strain 12419. S. salamae encode the Salmonella pathogenicity island (SPI)-1; SPI-2 and the locus of enterocyte effacement (LEE) T3SSs...
October 10, 2016: Infection and Immunity
Efrat Gottlieb-Abraham, Orit Gutman, Govind M Pai, Ignacio Rubio, Yoav I Henis
The interactions of Src family kinases (SFKs) with the plasma membrane are crucial for their activity. They depend on their fatty-acylated N-termini, containing N-myristate and either a polybasic cluster (in Src) or palmitoylation sites (e.g., Fyn). To investigate the roles of these moieties in SFK membrane association, we employed FRAP beam-size analysis to study the membrane interactions of c-Src-GFP or Fyn-GFP fatty-acylation mutants. Our studies showed for the first time that the membrane association of Fyn is more stable than that of Src, an effect lost in a Fyn mutant lacking the palmitoylation sites...
October 12, 2016: Molecular Biology of the Cell
Hitoshi Nakayama, Hidetake Kurihara, Yasu S Morita, Taroh Kinoshita, Laura Mauri, Alessandro Prinetti, Sandro Sonnino, Noriko Yokoyama, Hideoki Ogawa, Kenji Takamori, Kazuhisa Iwabuchi
Pathogenic mycobacteria use virulence factors, including mannose-capped lipoarabinomannan (ManLAM), to survive in host phagocytic cells, such as neutrophils. We assessed the roles of lactosylceramide (LacCer, CDw17)-enriched lipid rafts in the phagocytosis of mycobacteria by human neutrophils and in the intracellular fate of phagocytosed mycobacteria. We showed that the association of the Src family kinase (SFK) Lyn with C24 fatty acid chain-containing LacCer was essential for the phagocytosis of mycobacteria by neutrophils...
October 11, 2016: Science Signaling
Nicolas Gaboriaud-Kolar, Vasillios Myrianthopoulos, Konstantina Vougogiannopoulou, Panagiotis Gerolymatos, David A Horne, Richard Jove, Emmanuel Mikros, Sangkil Nam, Alexios-Leandros Skaltsounis
Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of "Danggui Longhui Wan", a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 μM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range...
October 11, 2016: Journal of Natural Products
MacRae F Linton, Vladimir R Babaev, Jiansheng Huang, Edward F Linton, Huan Tao, Patricia G Yancey
Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes...
October 8, 2016: Circulation Journal: Official Journal of the Japanese Circulation Society
Boon Siang Nicholas Tan, Joly Kwek, Chong Kum Edwin Wong, Nicholas J Saner, Charlotte Yap, Fernando Felquer, Michael B Morris, David K Gardner, Peter D Rathjen, Joy Rathjen
Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells...
2016: PloS One
Wenda Zhang, Ting Ma, Shanshan Li, Yanwei Yang, Jianpeng Guo, Wenying Yu, Lingyi Kong
STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50 range in 0.33-0.75 μM in various cancer cell lines...
September 22, 2016: European Journal of Medicinal Chemistry
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