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https://www.readbyqxmd.com/read/28921811/a-role-for-the-non-receptor-tyrosine-kinase-ack1-in-tnf-alpha-mediated-apoptosis-and-proliferation-in-human-intestinal-epithelial-caco-2-cells
#1
Xinmei Zhao, Chaolan Lv, Shenbo Chen, Fachao Zhi
The roles of tumor necrosis factor alpha (TNF-alpha) and its mediators in cellular processes related to intestinal diseases remain elusive. In this study, we aimed to determine the biological role of activated Cdc42-associated kinase 1 (ACK1) in TNF-alpha-mediated apoptosis and proliferation in Caco-2 cells. ACK1 expression was knocked down using ACK1-specific siRNAs, and ACK1 activity was disrupted using a small molecule ACK1 inhibitor. The Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (TUNEL) and the BrdU incorporation assays were used to measure apoptosis and cell proliferation, respectively...
September 16, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28874467/an-evolutionarily-conserved-pathway-essential-for-orsay-virus-infection-of-caenorhabditis-elegans
#2
Hongbing Jiang, Kevin Chen, Luis E Sandoval, Christian Leung, David Wang
Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280...
September 5, 2017: MBio
https://www.readbyqxmd.com/read/28739485/hsp90-is-necessary-for-the-ack1-dependent-phosphorylation-of-stat1-and-stat3
#3
Nisintha Mahendrarajah, Marina E Borisova, Sigrid Reichardt, Maren Godmann, Andreas Sellmer, Siavosh Mahboobi, Andrea Haitel, Katharina Schmid, Lukas Kenner, Thorsten Heinzel, Petra Beli, Oliver H Krämer
Signal transducers and activators of transcription (STATs) are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of STAT1 and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of STAT1 in transformed kidney cells. These processes are associated with STAT1-dependent gene expression and an interaction between endogenous STAT1 and ACK1...
November 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28609657/ack1-tnk2-regulates-histone-h4-tyr88-phosphorylation-and-ar-gene-expression-in-castration-resistant-prostate-cancer
#4
Kiran Mahajan, Pavani Malla, Harshani R Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J Lawrence, Nupam P Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription...
June 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28188290/activated-cdc42-associated-kinase-1-ack1-binds-the-sterile-%C3%AE-motif-sam-domain-of-the-adaptor-slp-76-and-phosphorylates-proximal-tyrosines
#5
Youg R Thaker, Asha Recino, Monika Raab, Asma Jabeen, Maja Wallberg, Nelson Fernandez, Christopher E Rudd
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, "3Y") as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76...
April 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28055971/src-promotes-castration-recurrent-prostate-cancer-through-androgen-receptor-dependent-canonical-and-non-canonical-transcriptional-signatures
#6
Indranil Chattopadhyay, Jianmin Wang, Maochun Qin, Lingqiu Gao, Renae Holtz, Robert L Vessella, Robert W Leach, Irwin H Gelman
Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27926694/involvement-of-activated-cdc42-kinase1-in-colitis-and-colorectal-neoplasms
#7
Chaolan Lv, Xinmei Zhao, Hongxiang Gu, Liyun Huang, Sanxi Zhou, Fachao Zhi
BACKGROUND Activated Cdc42 kinase1 (ACK1) is a non-receptor tyrosine kinase which is critical for cell survival, proliferation, and migration. Genomic amplification of ACK1 has been reported in multiple human cancers. We aimed to investigate ACK1 protein expression in colorectal mucosa with inflammation and neoplasm, and to evaluate its correlation with disease activity and severity. MATERIAL AND METHODS A total of 250 individuals who underwent total colonoscopy were collected randomly from January 2007 to May 2013 in Nanfang Hospital, Guangzhou, China...
December 7, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27904688/molecular-mechanism-of-prostate-cancer-cell-apoptosis-induced-by-busulfan-via-adjustment-of-androgen-receptor-phosphatization
#8
Jun Liu, Guojun Jiang, Aiping Yang, Guohui Yang, Wenjuan Yang, Yi Fang
OBJECTIVE: To probe killing effect of busulfan to prostate cancer cell without androgen and the influence of androgen receptor phosphatization and analyze its molecular mechanism. METHODS: prostate cancer cell line 22RV1, LAPC4 and LNCaP treated with busulfan under androgen-free condition underwent CCK-8 examination to probe killing ability of the medicine. Flow cytometry was used to check the influence of busulfan on apoptosis rate of prostate cancer cell line LAPC4...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27902967/the-non-receptor-tyrosine-kinase-tnk2-ack1-is-a-novel-therapeutic-target-in-triple-negative-breast-cancer
#9
Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Dhanashree S Kelkar, Mustafa A Barbhuiya, Pamela L Rojas, Vered Stearns, Edward Gabrielson, Pavani Malla, Saraswati Sukumar, Nupam P Mahajan, Akhilesh Pandey
Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/27782307/estimation-of-relative-free-energies-of-binding-using-pre-computed-ensembles-based-on-the-single-step-free-energy-perturbation-and-the-site-identification-by-ligand-competitive-saturation-approaches
#10
E Prabhu Raman, Sirish Kaushik Lakkaraju, Rajiah Aldrin Denny, Alexander D MacKerell
Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, although they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods...
June 5, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/27576506/histone-deacetylase-inhibitors-induce-proteolysis-of-activated-cdc42-associated-kinase-1-in-leukemic-cells
#11
Nisintha Mahendrarajah, Ramin Paulus, Oliver H Krämer
PURPOSE: Activated CDC42-associated kinase-1 (ACK1/TNK2) and epigenetic regulators of the histone deacetylase (HDAC) family regulate the proliferation and survival of leukemic cells. 18 HDACs fall into four classes (I-IV). We tested the impact of clinically relevant histone deacetylase inhibitors (HDACi) on ACK1 and if such drugs combine favorably with the therapeutically used ACK1 inhibitor Dasatinib. METHODS: We applied the broad-range HDACi Panobinostat/LBH589 and the class I HDAC-specific inhibitor Entinostat/MS-275 to various acute and chronic myeloid leukemia cells (AML/CML)...
November 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27387461/auto-thiophosphorylation-activity-of-src-tyrosine-kinase
#12
M Zulema Cabail, Emily I Chen, Antonius Koller, W Todd Miller
BACKGROUND: Intermolecular autophosphorylation at Tyr416 is a conserved mechanism of activation among the members of the Src family of nonreceptor tyrosine kinases. Like several other tyrosine kinases, Src can catalyze the thiophosphorylation of peptide and protein substrates using ATPγS as a thiophosphodonor, although the efficiency of the reaction is low. RESULTS: Here, we have characterized the ability of Src to auto-thiophosphorylate. Auto-thiophosphorylation of Src at Tyr416 in the activation loop proceeds efficiently in the presence of Ni(2+), resulting in kinase activation...
July 7, 2016: BMC Biochemistry
https://www.readbyqxmd.com/read/26923695/novel-2-4-diaminopyrimidines-bearing-tetrahydronaphthalenyl-moiety-against-anaplastic-lymphoma-kinase-alk-synthesis-in-vitro-ex-vivo-and-in-vivo-efficacy-studies
#13
Dawn Song, Minji Lee, Chi Hoon Park, Sunjoo Ahn, Chang Soo Yun, Chong Ock Lee, Hyoung Rae Kim, Jong Yeon Hwang
A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy...
April 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26621748/ack1-is-a-dopamine-transporter-endocytic-brake-that-rescues-a-trafficking-dysregulated-adhd-coding-variant
#14
Sijia Wu, Karl D Bellve, Kevin E Fogarty, Haley E Melikian
The dopamine (DA) transporter (DAT) facilitates high-affinity presynaptic DA reuptake that temporally and spatially constrains DA neurotransmission. Aberrant DAT function is implicated in attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is a major psychostimulant target, and psychostimulant reward strictly requires binding to DAT. DAT function is acutely modulated by dynamic membrane trafficking at the presynaptic terminal and a PKC-sensitive negative endocytic mechanism, or "endocytic brake," controls DAT plasma membrane stability...
December 15, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26536663/ack1-overexpression-promotes-metastasis-and-indicates-poor-prognosis-of-hepatocellular-carcinoma
#15
RANDOMIZED CONTROLLED TRIAL
Xiong Lei, Yun-Feng Li, Guo-Dong Chen, Di-Peng Ou, Xiao-Xin Qiu, Chao-Hui Zuo, Lian-Yue Yang
Despite the substantial data supporting the oncogenic role of Ack1, the predictive value and biologic role of Ack1 in hepatocellular carcinoma (HCC) metastasis remains unknown. In this study, both correlations of Ack1 expression with prognosis of HCC, and the role of Ack1 in metastasis of HCC were investigated in vitro and in vivo. Our results showed that Ack1 was overexpressed in human HCC tissues and cell lines. High Ack1 expression was associated with HCC metastasis and determined as a significant and independent prognostic factor for HCC after liver resection...
December 1, 2015: Oncotarget
https://www.readbyqxmd.com/read/26025205/the-critical-role-of-akt-in-cardiovascular-function
#16
REVIEW
Prasanna Abeyrathna, Yunchao Su
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1...
November 2015: Vascular Pharmacology
https://www.readbyqxmd.com/read/25950519/mutation-of-androgen-receptor-n-terminal-phosphorylation-site-tyr-267-leads-to-inhibition-of-nuclear-translocation-and-dna-binding
#17
Mehmet Karaca, Yuanbo Liu, Zhentao Zhang, Dinuka De Silva, Joel S Parker, H Shelton Earp, Young E Whang
Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain...
2015: PloS One
https://www.readbyqxmd.com/read/25945695/activated-cdc42-associated-kinase-is-up-regulated-in-non-small-cell-lung-cancer-and-necessary-for-fgfr-mediated-akt-activation
#18
Fengqing Hu, Hongcheng Liu, Xiao Xie, Ju Mei, Mingsong Wang
Activated cdc42-associated tyrosine kinase 1 (ACK1) has been reported to be implicated in non-small-cell lung cancer (NSCLC). However, the expression pattern and biological functions of ACK1 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of ACK1 was significantly up-regulated in NSCLC samples compared to their adjacent normal tissues. Meanwhile, the expression of ACK1 was inversely correlated with the survival of NSCLC patients. Moreover, in the biological function studies, ACK1 was further validated to promote the growth, migration, and metastasis of NSCLC cells in vitro and in vivo...
May 2016: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/25833960/identification-of-novel-therapeutic-targets-in-acute-leukemias-with-nras-mutations-using-a-pharmacologic-approach
#19
Atsushi Nonami, Martin Sattler, Ellen Weisberg, Qingsong Liu, Jianming Zhang, Matthew P Patricelli, Amanda L Christie, Amy M Saur, Nancy E Kohl, Andrew L Kung, Hojong Yoon, Taebo Sim, Nathanael S Gray, James D Griffin
Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia...
May 14, 2015: Blood
https://www.readbyqxmd.com/read/25699576/development-of-novel-ack1-tnk2-inhibitors-using-a-fragment-based-approach
#20
Harshani R Lawrence, Kiran Mahajan, Yunting Luo, Daniel Zhang, Nathan Tindall, Miles Huseyin, Harsukh Gevariya, Sakib Kazi, Sevil Ozcan, Nupam P Mahajan, Nicholas J Lawrence
The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process...
March 26, 2015: Journal of Medicinal Chemistry
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