Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer
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LY2801653 Is an Orally Bioavailable Multi-Kinase Inhibitor with Potent
Invest New Drugs (2013) 31:833–844 DOI 10.1007/s10637-012-9912-9 PRECLINICAL STUDIES LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models S. Betty Yan & Victoria L. Peek & Rose Ajamie & Sean G. Buchanan & Jeremy R. Graff & Steven A. Heidler & Yu-Hua Hui & Karen L. Huss & Bruce W. Konicek & Jason R. Manro & Chuan Shih & Julie A. Stewart & Trent R. Stewart & Stephanie L. Stout & Mark T. Uhlik & Suzane L. Um & Yong Wang & Wenjuan Wu & Lei Yan & Wei J. Yang & Boyu Zhong & Richard A. Walgren Received: 19 October 2012 /Accepted: 3 December 2012 /Published online: 29 December 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com Summary The HGF/MET signaling pathway regulates a of a potent, orally bioavailable, small-molecule inhibitor wide variety of normal cellular functions that can be subverted LY2801653 targeting MET kinase. LY2801653 is a type-II to support neoplasia, including cell proliferation, survival, ATP competitive, slow-off inhibitor of MET tyrosine kinase apoptosis, scattering and motility, invasion, and angiogenesis. with a dissociation constant (Ki) of 2 nM, a pharmacodynamic −1 MET over-expression (with or without gene amplification), residence time (Koff) of 0.00132 min and t1/2 of 525 min. aberrant autocrine or paracrine ligand production, and mis- LY2801653 demonstrated in vitro effects on MET pathway- sense MET mutations are mechanisms that lead to activation dependent cell scattering and cell proliferation; in vivo anti- of the MET pathway in tumors and are associated with poor tumor effects in MET amplified (MKN45), MET autocrine prognostic outcome. -
Crystal Structure of the Kinase Domain of Mertk in Complex with AZD7762 Provides Clues for Structure-Based Drug Development
International Journal of Molecular Sciences Article Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development Tae Hyun Park 1,2 , Seung-Hyun Bae 1,3 , Seoung Min Bong 1, Seong Eon Ryu 2, Hyonchol Jang 1,3 and Byung Il Lee 1,3,* 1 Research Institute, National Cancer Center, Goyang, 10408 Gyeonggi, Korea; [email protected] (T.H.P.); [email protected] (S.-H.B.); [email protected] (S.M.B.); [email protected] (H.J.) 2 Department of Bioengineering, Hanyang University, 04763 Seoul, Korea; [email protected] 3 Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, 10408 Gyeonggi, Korea * Correspondence: [email protected]; Tel.: +82-31-920-2223; Fax: +82-31-920-2006 Received: 29 August 2020; Accepted: 21 October 2020; Published: 23 October 2020 Abstract: Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines. -
Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer Running Title
Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Uvyr)Thvp ru v rpr hv h r hpvhrq vu rhhv v vh py rphy phpr Svt vyr) 6u ) " #$ % & '$ $( $)*# $ ,$$ - ./ 0 1 " , $'2 / ' - , $$03$, 4, 5$ $ 6 7$ % & 8 8$ 9 6ssvyvhv) . 8 : .2 $ 5 1 $ ; $ ;# < %. 8 : ., , $ ;# $ < -: . $, 8 $ . . 8 ; $ ;# /. 8 : . $; $ ;# < 0= $ 1 2 . , >2,, $ ?&, $ 2 . & $ , $@ ABA%B, $ < 4: . $ $ $ ; $ ;# < 6: .2 $ 5 1 $ .@ $ $ $ = $ ; $ ;# < Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. & 8 * $$ < 9& $8 C 8 < 8$ D< < 8syvp s vr rC & . $@ $, $ ', $E $ . $ 8$:7'@ < % Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6i hpC& 8 . . $ $ >? $ <& . # $# . $ $ .464A6 22)2 . $. E<& # $ >?. $ . ). $ . ) . $$ 222 2 < $ $ . @ . <& 8$. $ ., ::)$$@,. ) $ ),@$$<F .8 222 . , $) ,::)$$ ), $E <& 8# # $8 , < - Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 20, 2017; DOI: 10.1158/0008-5472.CAN-16-1921 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. D qpv #$ .$$) $ .. 8 >&5?>?<& . 8@ #$ $#$ # $ 8$ .8 . -
MERTK Antibody Catalog Number: MKT-101AP Lot Number: General Information
FabGennix International, Inc. 9191 Kyser Way Bldg. 4 Suite 402 Frisco, TX 75033 Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Rabbit Polyclonal Anti-MERTK antibody Catalog Number: MKT-101AP Lot Number: General Information Product MERTK Antibody Description Affinity Purified Human cellular proto-oncogene (c- mer) mRNA Antibody C-epitope Accession # Uniprot: Q12866 GenBank: U08023.1 Verified Applications CM, ELISA, ICC, IF, IHC, IP, WB Species Cross Reactivity Human, Mouse, Rat Host Rabbit Immunogen Synthetic peptide taken within amino acid region 900-994 on MerTK protein. Alternative Nomenclature c mer proto oncogene tyrosine kinase antibody, cMER antibody, Eyk antibody, MER antibody, MER receptor tyrosine kinase antibody, MERK antibody, MERPEN antibody, Mertk antibody, MERTK c-mer proto-oncogene tyrosine kinase antibody, MGC133349 antibody, nmf12 antibody, Nyk antibody, Proto oncogene tyrosine protein kinase MER antibody, Receptor tyrosine kinase MerTK antibody, RP38 antibody, STK kinase antibody, Tyrosine-protein kinase Mer antibody Physical Properties Quantity 100 µg Volume 200 µl Form Affinity Purified Immunoglobulins Determinant C-epitope Immunoglobulin & Concentration 0.75 mg/ml IgG in antibody stabilization buffer Storage Store at -20⁰C for long term storage. Related Products Catalog # BIOTIN-Conjugated MKT100-BIOTIN FITC-Conjugated MKT100-FITC Antigenic Blocking Peptide P-MKT100 Western Blot Positive Control PC-MKT Tel: (214)-387-8105, 1-800-786-1236 Fax: (214)-387-8105 Email: [email protected] Web: www.FabGennix.com Recommended Dilutions DOT Blot 1:10,000 ELISA 1:10,000 Immunocytochemistry 1:200 Immunofluorescence 1:200 Immunohistochemistry 1:200 Immunoprecipitation 1:200 Western Blot 1:750 Application Verification: WB using MKT-101AP and human RPE cells. -
Activation of Transmembrane Cell-Surface Receptors Via a Common Mechanism? the ‘‘Rotation Model’’
Insights & Perspectives Hypotheses Activation of transmembrane cell-surface receptors via a common mechanism? The ‘‘rotation model’’ Ichiro N. Maruyama It has long been thought that transmembrane cell-surface receptors, such as typically consist of an extracellular receptor tyrosine kinases and cytokine receptors, among others, are activated by domain (ECD) and an intracellular ligand binding through ligand-induced dimerization of the receptors. However, domain (ICD) separated by a single transmembrane domain (TMD), with there is growing evidence that prior to ligand binding, various transmembrane the exception of bacterial receptors receptors have a preformed, yet inactive, dimeric structure on the cell surface. such as the aspartate receptor (Tar) Various studies also demonstrate that during transmembrane signaling, ligand and the serine receptor (Tsr), which binding to the extracellular domain of receptor dimers induces a rotation of have another TMD at their amino transmembrane domains, followed by rearrangement and/or activation of termini. Ligand binding to their ECDs often regulates kinases that are either intracellular domains. The paper here describes transmembrane cell-surface integrated into the receptor ICD, or receptors that are known or proposed to exist in dimeric form prior toligand binding, physically associated with the ICD. and discusses how these preformed dimers are activated by ligand binding. Apart from receptors that initiate signaling pathways inside cells via Keywords: tyrosine phosphorylation, there are .cytokine; dimerization; ligand binding; preformed dimer; transmembrane receptors in bacteria, fungi, and plants signaling; tyrosine kinase that phosphorylate histidine residues upon ligand binding. Furthermore, natriuretic peptide receptors, which are receptor-type guanylyl cyclases, Introduction cell membranes to the cytoplasm, and produce cGMP upon peptide binding. -
Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M
Published OnlineFirst May 26, 2016; DOI: 10.1158/0008-5472.CAN-16-0058 Cancer Therapeutics, Targets, and Chemical Biology Research Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies Timothy M. Shaver1,2, Brian D. Lehmann1,2, J. Scott Beeler1,2, Chung-I Li3, Zhu Li1,2, Hailing Jin1,2, Thomas P. Stricker4, Yu Shyr5,6, and Jennifer A. Pietenpol1,2 Abstract Triple-negative breast cancer (TNBC) and other molecularly discovered a clinical occurrence and cell line model of the target- heterogeneous malignancies present a significant clinical chal- able FGFR3–TACC3 fusion in TNBC. Expanding our analysis to lenge due to a lack of high-frequency "driver" alterations amena- other malignancies, we identified a diverse array of novel and ble to therapeutic intervention. These cancers often exhibit geno- known hybrid transcripts, including rearrangements between mic instability, resulting in chromosomal rearrangements that noncoding regions and clinically relevant genes such as ALK, affect the structure and expression of protein-coding genes. How- CSF1R, and CD274/PD-L1. The over 1,000 genetic alterations ever, identification of these rearrangements remains technically we identified highlight the importance of considering noncod- challenging. Using a newly developed approach that quantita- ing gene rearrangement partners, and the targetable gene tively predicts gene rearrangements in tumor-derived genetic fusions identified in TNBC demonstrate the need to advance material, we identified -
Mertk Regulates Thymic Selection of Autoreactive T Cells
MerTK regulates thymic selection of autoreactive T cells Mark A. Walleta, Rafael R. Floresa, Yaming Wanga, Zuoan Yia, Charles J. Krogera, Clayton E. Mathewsb, H. Shelton Earpc,d, Glenn Matsushimaa,c,e, Bo Wanga, and Roland Tischa,c,1 aDepartment of Microbiology and Immunology, cUNC Lineberger Comprehensive Cancer Center, dDepartment of Medicine and Pharmacology, eUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599-7020; and bDepartment of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610 Communicated by Hugh O. McDevitt, Stanford University, Stanford, CA, January 23, 2009 (received for review September 30, 2008) T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) Our group and others demonstrated that the Mer tyrosine are believed to be the result in part of inefficient negative selection kinase (MerTK) negatively regulates antigen presenting cells of self-specific thymocytes. However, the events regulating thymic (APC) such as DC and macrophages (M) (18–21). MerTK negative selection are not fully understood. In the current study, belongs to a family of receptor tyrosine kinases (RTKs) con- we demonstrate that nonobese diabetic (NOD) mice lacking ex- sisting of Axl and Tyro3 (22, 23). Mice lacking expression of all pression of the Mer tyrosine kinase (MerTK) have reduced inflam- 3 RTKs have hyperactive APC in the periphery, resulting in mation of the pancreatic islets and fail to develop diabetes. systemic autoimmunity characterized by T cell infiltrates in Furthermore, NOD mice deficient in MerTK expression (Mer؊/؊) several tissues (24). In addition to DC and M, MerTK is exhibit a reduced frequency of  cell-specific T cells independent of expressed by NK T cells, NK cells, epithelia and endothelia cell immunoregulatory effectors. -
Eph Receptor Signalling: from Catalytic to Non-Catalytic Functions
Oncogene (2019) 38:6567–6584 https://doi.org/10.1038/s41388-019-0931-2 REVIEW ARTICLE Eph receptor signalling: from catalytic to non-catalytic functions 1,2 1,2 3 1,2 1,2 Lung-Yu Liang ● Onisha Patel ● Peter W. Janes ● James M. Murphy ● Isabelle S. Lucet Received: 20 March 2019 / Revised: 23 July 2019 / Accepted: 24 July 2019 / Published online: 12 August 2019 © The Author(s) 2019. This article is published with open access Abstract Eph receptors, the largest subfamily of receptor tyrosine kinases, are linked with proliferative disease, such as cancer, as a result of their deregulated expression or mutation. Unlike other tyrosine kinases that have been clinically targeted, the development of therapeutics against Eph receptors remains at a relatively early stage. The major reason is the limited understanding on the Eph receptor regulatory mechanisms at a molecular level. The complexity in understanding Eph signalling in cells arises due to following reasons: (1) Eph receptors comprise 14 members, two of which are pseudokinases, EphA10 and EphB6, with relatively uncharacterised function; (2) activation of Eph receptors results in dimerisation, oligomerisation and formation of clustered signalling centres at the plasma membrane, which can comprise different combinations of Eph receptors, leading to diverse downstream signalling outputs; (3) the non-catalytic functions of Eph receptors have been overlooked. This review provides a structural perspective of the intricate molecular mechanisms that 1234567890();,: 1234567890();,: drive Eph receptor signalling, and investigates the contribution of intra- and inter-molecular interactions between Eph receptors intracellular domains and their major binding partners. We focus on the non-catalytic functions of Eph receptors with relevance to cancer, which are further substantiated by exploring the role of the two pseudokinase Eph receptors, EphA10 and EphB6. -
Systemic Analysis of Tyrosine Kinase Signaling Reveals a Common Adaptive Response Program in a HER2-Positive Breast Cancer
Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Schwill, Martin et al. "Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer." Science Signaling 12, 565 (January 2019): eaau2875 © 2019 The Author(s) As Published https://dx.doi.org/10.1126/scisignal.aau2875 Publisher American Association for the Advancement of Science (AAAS) Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/125489 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Sci Signal Manuscript Author . Author manuscript; Manuscript Author available in PMC 2019 July 22. Published in final edited form as: Sci Signal. ; 12(565): . doi:10.1126/scisignal.aau2875. Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer Martin Schwill1, Rastislav Tamaskovic1, Aaron S. Gajadhar2, Florian Kast1, Forest M. White2, and Andreas Plückthun1,* 1Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland 2Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Abstract Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promotes the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those which induce only temporary cell cycle arrest or apoptosis in HER2-overexpressing cancers. -
Mertk Inhibition Is a Novel Therapeutic Approach for Glioblastoma Multiforme
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 5, No. 5 MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme Kristina H. Knubel1, Ben M. Pernu1, Alexandra Sufit1, Sarah Nelson1, Angela M. Pierce1, Amy K. Keating1 1 Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA Correspondence to: Amy K Keating, email: [email protected] Keywords: MerTK, Axl, glioma, Foretinib, intracranial model Received: January 16, 2014 Accepted: March 10, 2014 Published: March 12, 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: Glioblastoma is an aggressive tumor that occurs in both adult and pediatric patients and is known for its invasive quality and high rate of recurrence. Current therapies for glioblastoma result in high morbidity and dismal outcomes. The TAM subfamily of receptor tyrosine kinases includes Tyro3, Axl, and MerTK. Axl and MerTK exhibit little to no expression in normal brain but are highly expressed in glioblastoma and contribute to the critical malignant phenotypes of survival, chemosensitivity and migration. We have found that Foretinib, a RTK inhibitor currently in clinical trial, inhibited phosphorylation of TAM receptors, with highest efficacy against MerTK, and blocked downstream activation of Akt and Erk in adult and pediatric glioblastoma cell lines, findings that are previously unreported. Survival, proliferation, migration, and collagen invasion were hindered in vitro. Foretinib treatment in vivo abolished MerTK phosphorylation and reduced tumor growth 3-4 fold in a subcutaneous mouse model. -
Tie2 and Eph Receptor Tyrosine Kinase Activation and Signaling
Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Tie2 and Eph Receptor Tyrosine Kinase Activation and Signaling William A. Barton1, Annamarie C. Dalton1, Tom C.M. Seegar1, Juha P. Himanen2, and Dimitar B. Nikolov2 1Department of Biochemistry and Molecular Biology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298 2Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065 Correspondence: [email protected] The Eph and Tie cell surface receptors mediate a variety of signaling events during develop- ment and in the adult organism. As other receptor tyrosine kinases, they are activated on binding of extracellular ligands and their catalytic activity is tightly regulated on multiple levels. The Eph and Tie receptors display some unique characteristics, including the require- ment of ligand-induced receptor clustering for efficient signaling. Interestingly, both Ephs and Ties can mediate different, even opposite, biological effects depending on the specific ligand eliciting the response and on the cellular context. Here we discuss the structural features of these receptors, their interactions with various ligands, as well as functional implications for downstream signaling initiation. The Eph/ephrin structures are already well reviewed and we only provide a brief overview on the initial binding events. We go into more detail discussing the Tie-angiopoietin structures and recognition. ANGIOPOIETINS AND TIE2 In contrast tovasculogenesis, angiogenesis is asculogenesis and angiogenesis are distinct continually required in the adult for wound re- Vcellular processes essential to the creation of pairand remodeling of reproductive tissues dur- the adult vasculature. In early embryonic devel- ing female menstruation. -
Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy
cancers Review Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy 1,2, 3,4 1 2 3, Charles Pottier * , Margaux Fresnais , Marie Gilon , Guy Jérusalem ,Rémi Longuespée y 1, and Nor Eddine Sounni y 1 Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University Hospital of Liège, 4000 Liège, Belgium; [email protected] (M.G.); [email protected] (N.E.S.) 2 Department of Medical Oncology, University Hospital of Liège, 4000 Liège, Belgium; [email protected] 3 Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, 69120 Heidelberg, Germany; [email protected] (M.F.); [email protected] (R.L.) 4 German Cancer Consortium (DKTK)-German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany * Correspondence: [email protected] Equivalent contribution. y Received: 17 January 2020; Accepted: 16 March 2020; Published: 20 March 2020 Abstract: Receptor tyrosine kinases (RTKs) are key regulatory signaling proteins governing cancer cell growth and metastasis. During the last two decades, several molecules targeting RTKs were used in oncology as a first or second line therapy in different types of cancer. However, their effectiveness is limited by the appearance of resistance or adverse effects. In this review, we summarize the main features of RTKs and their inhibitors (RTKIs), their current use in oncology, and mechanisms of resistance. We also describe the technological advances of artificial intelligence, chemoproteomics, and microfluidics in elaborating powerful strategies that could be used in providing more efficient and selective small molecules inhibitors of RTKs.