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Emeline Gauthiez, Ines Habfast-Robertson, Sina Rüeger, Zoltan Kutalik, Vincent Aubert, Thomas Berg, Andreas Cerny, Meri Gorgievski, Jacob George, Markus H Heim, Raffaele Malinverni, Darius Moradpour, Beat Müllhaupt, Francesco Negro, David Semela, Nasser Semmo, Jean Villard, Stéphanie Bibert, Pierre-Yves Bochud
While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data...
March 6, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
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
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
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
Gajanan Sathe, Sneha M Pinto, Nazia Syed, Vishalakshi Nanjappa, Hitendra S Solanki, Santosh Renuse, Sandip Chavan, Aafaque Ahmad Khan, Arun H Patil, Raja Sekhar Nirujogi, Bipin Nair, Premendu Prakash Mathur, T S Keshava Prasad, Harsha Gowda, Aditi Chatterjee
BACKGROUND: Curcumin, derived from the rhizome Curcuma longa, is a natural anti-cancer agent and has been shown to inhibit proliferation and survival of tumor cells. Although the anti-cancer effects of curcumin are well established, detailed understanding of the signaling pathways altered by curcumin is still lacking. In this study, we carried out SILAC-based quantitative proteomic analysis of a HNSCC cell line (CAL 27) to investigate tyrosine signaling in response to curcumin. RESULTS: Using high resolution Orbitrap Fusion Tribrid Fourier transform mass spectrometer, we identified 627 phosphotyrosine sites mapping to 359 proteins...
2016: Clinical Proteomics
Julia E Maxson, Melissa L Abel, Jinhua Wang, Xianming Deng, Sina Reckel, Samuel B Luty, Huahang Sun, Julie Gorenstein, Seamus B Hughes, Daniel Bottomly, Beth Wilmot, Shannon K McWeeney, Jerald Radich, Oliver Hantschel, Richard E Middleton, Nathanael S Gray, Brian J Druker, Jeffrey W Tyner
The amount of genomic information about leukemia cells currently far exceeds our overall understanding of the precise genetic events that ultimately drive disease development and progression. Effective implementation of personalized medicine will require tools to distinguish actionable genetic alterations within the complex genetic landscape of leukemia. In this study, we performed kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia and chronic myelomonocytic leukemia...
January 1, 2016: Cancer Research
Janice L Farlow, Laurie A Robak, Kurt Hetrick, Kevin Bowling, Eric Boerwinkle, Zeynep H Coban-Akdemir, Tomasz Gambin, Richard A Gibbs, Shen Gu, Preti Jain, Joseph Jankovic, Shalini Jhangiani, Kaveeta Kaw, Dongbing Lai, Hai Lin, Hua Ling, Yunlong Liu, James R Lupski, Donna Muzny, Paula Porter, Elizabeth Pugh, Janson White, Kimberly Doheny, Richard M Myers, Joshua M Shulman, Tatiana Foroud
IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained...
January 2016: JAMA Neurology
Patrick Coit, Paul Renauer, Matlock A Jeffries, Joan T Merrill, W Joseph McCune, Kathleen Maksimowicz-McKinnon, Amr H Sawalha
Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement...
July 2015: Journal of Autoimmunity
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
Altangerel Otgonbat, Mingfeng Zhao
OBJECTIVE: To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia (CNL). DATA SOURCES: Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms "chronic neutrophilic leukemia" and "diagnosis" were used for the literature search. STUDY SELECTION: We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL...
2014: Chinese Medical Journal
Meghan L Rudd, Hassan Mohamed, Jessica C Price, Andrea J O'Hara, Matthieu Le Gallo, Mary Ellen Urick, Pedro Cruz, Suiyuan Zhang, Nancy F Hansen, Andrew K Godwin, Dennis C Sgroi, Tyra G Wolfsberg, James C Mullikin, Maria J Merino, Daphne W Bell
BACKGROUND: Endometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets. METHODS: In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs...
November 26, 2014: BMC Cancer
K Mahajan, N P Mahajan
Deregulated tyrosine kinase signaling alters cellular homeostasis to drive cancer progression. The emergence of a non-receptor tyrosine kinase (non-RTK), ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) as an oncogenic kinase, has uncovered novel mechanisms by which tyrosine kinase signaling promotes cancer progression. Although early studies focused on ACK1 as a cytosolic effector of activated transmembrane RTKs, wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator...
August 6, 2015: Oncogene
Jiannan Zhang, Tao Chen, Qin Mao, Jinbo Lin, Jun Jia, Shanquan Li, Wenhao Xiong, Yingying Lin, Zhiqiang Liu, Xiaoyu Liu, Hailiang Zhao, Guisong Wang, Duo Zheng, Shuqi Qiu, Jianwei Ge
Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT...
April 15, 2015: International Journal of Cancer. Journal International du Cancer
Kiran Mahajan, Harshani R Lawrence, Nicholas J Lawrence, Nupam P Mahajan
Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor α (ER)-positive breast cancers. However, a subset of patients exhibiting overexpression of the HER2 receptor tyrosine kinase displays intrinsic resistance to tamoxifen therapy. Therefore, elucidating the mechanisms promoting the estrogen (E2)-independent ER-regulated gene transcription in tamoxifen-resistant breast tumors is essential to identify new therapeutic avenues to overcome drug resistance and ameliorate poor prognosis...
October 10, 2014: Journal of Biological Chemistry
Khairun I Abdul-Jalil, Katherine M Sheehan, Sinead Toomey, Jasmin Schmid, Jochen Prehn, Anthony O'Grady, Robert Cummins, Brian O'Neill, Deborah A McNamara, Joseph Deasy, Oscar Breathnach, Liam Grogan, Ailin Rogers, Glen Doherty, Des Winter, John Ryan, Sherif El-Masry, David Gibbons, Kieran Sheahan, Peter Gillen, Elaine W Kay, Bryan T Hennessy
BACKGROUND: Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes. METHODS: We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway-related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform...
August 2014: Annals of Surgical Oncology
Sylwia Jones, Debbie L Cunningham, Joshua Z Rappoport, John K Heath
Growth factor signalling regulates multiple cellular functions and its misregulation has been linked to the development and progression of cancer. Ack1 (activated Cdc42-associated kinase 1, also known as TNK2) is a non-receptor tyrosine kinase that has been implicated in trafficking and degradation of epidermal growth factor receptor (EGFR), yet its precise functions remain elusive. In this report, we investigate the role of Ack1 in EGFR trafficking and show that Ack1 partially colocalises to Atg16L-positive structures upon stimulation with EGF...
March 1, 2014: Journal of Cell Science
Kazuya Shinmura, Shinichiro Kiyose, Kiyoko Nagura, Hisaki Igarashi, Yusuke Inoue, Satoki Nakamura, Matsuyoshi Maeda, Megumi Baba, Hiroyuki Konno, Haruhiko Sugimura
BACKGROUNDS AND OBJECTIVES: We previously examined the amplification status of 10 kinase genes (PIK3CA, EPHB3, TNK2, PTK7, EGFR, MET, ERBB2, HCK, SRC, and AURKA) in gastric cancer (GC). This study aimed to determine the prognostic significance of these gene amplifications in GC. METHODS: A survival analysis was performed for GC patients. Since TNK2 amplification was identified as a prognostic marker in the analysis, we also examined the functional effect of TNK2 overexpression on gastric cells...
March 2014: Journal of Surgical Oncology
Yuki Hitomi, Erin L Heinzen, Simona Donatello, Hans-Henrik Dahl, John A Damiano, Jacinta M McMahon, Samuel F Berkovic, Ingrid E Scheffer, Benjamin Legros, Myriam Rai, Sarah Weckhuysen, Arvid Suls, Peter De Jonghe, Massimo Pandolfo, David B Goldstein, Patrick Van Bogaert, Chantal Depondt
We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation...
September 2013: Annals of Neurology
Julia E Maxson, Jason Gotlib, Daniel A Pollyea, Angela G Fleischman, Anupriya Agarwal, Christopher A Eide, Daniel Bottomly, Beth Wilmot, Shannon K McWeeney, Cristina E Tognon, J Blake Pond, Robert H Collins, Basem Goueli, Stephen T Oh, Michael W Deininger, Bill H Chang, Marc M Loriaux, Brian J Druker, Jeffrey W Tyner
BACKGROUND: The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms. METHODS: To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors...
May 9, 2013: New England Journal of Medicine
Kiran Mahajan, Domenico Coppola, Bhupendra Rawal, Y Ann Chen, Harshani R Lawrence, Robert W Engelman, Nicholas J Lawrence, Nupam P Mahajan
Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth...
June 22, 2012: Journal of Biological Chemistry
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