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Ruuth, Kristina
Publications (10 of 20) Show all publications
Thanikkal, E. J., Kumar Gahlot, D., Liu, J., Fredriksson Sundbom, M., Gurung, J. M., Ruuth, K., . . . Francis, M. S. (2019). The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM. Virulence, 10(1), 37-57
Open this publication in new window or tab >>The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM
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2019 (English)In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 10, no 1, p. 37-57Article in journal (Refereed) Published
Abstract [en]

The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two-component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM and directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site-directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2019
Keywords
Environmental stress responsiveness, gene expression control, metabolic networks, microbial behaviour, growth and survival, fitness
National Category
Microbiology Microbiology in the medical area
Research subject
Microbiology; Molecular Biology; Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-154425 (URN)10.1080/21505594.2018.1556151 (DOI)000453473300001 ()30518290 (PubMedID)
Funder
Swedish Research Council, 2009-3660Swedish Research Council, 2014-6652
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-03-05Bibliographically approved
Guan, J., Fransson, S., Siaw, J. T., Treis, D., Van den Eynden, J., Chand, D., . . . Hallberg, B. (2018). Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma o the ALK inhibitor ceritinib. Cold Spring Harbor Molecular Case Studies, 4(4), Article ID a002550.
Open this publication in new window or tab >>Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma o the ALK inhibitor ceritinib
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2018 (English)In: Cold Spring Harbor Molecular Case Studies, ISSN 2373-2873, Vol. 4, no 4, article id a002550Article in journal (Refereed) Published
Abstract [en]

Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.

Place, publisher, year, edition, pages
Cold Spring Harbor Laboratory Press (CSHL), 2018
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154087 (URN)10.1101/mcs.a002550 (DOI)000450957400001 ()29907598 (PubMedID)
Funder
Swedish Cancer Society, TMCAN2015/794Swedish Cancer Society, BHCAN15/775Swedish Cancer Society, RHP CAN15/391Swedish Cancer Society, PK CAN16/3625Swedish Childhood Cancer Foundation, TM PR2016-0147Swedish Childhood Cancer Foundation, BH 2015-80Swedish Childhood Cancer Foundation, 2014-150Swedish Childhood Cancer Foundation, RHP 2015-96Swedish Childhood Cancer Foundation, PK PR2014-0084Swedish Childhood Cancer Foundation, JG 2016-0011Swedish Childhood Cancer Foundation, SF 15-0061Swedish Childhood Cancer Foundation, DT 12-009Swedish Childhood Cancer Foundation, 12-002Swedish Research Council, RHP 2015-04466Swedish Research Council, TM 521-2014-3031Swedish Research Council, PK 2014-3036Swedish Research Council, BH 521-2012-2831Swedish Foundation for Strategic Research , RB13-0204Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, RHP2016
Available from: 2018-12-12 Created: 2018-12-12 Last updated: 2018-12-12Bibliographically approved
Van den Eynden, J., Umapathy, G., Ashouri, A., Cervantes-Madrid, D., Szydzik, J., Ruuth, K., . . . Hallberg, B. (2018). Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways. Science Signaling, 11(557), Article ID eaar5680.
Open this publication in new window or tab >>Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways
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2018 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 11, no 557, article id eaar5680Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma is a common pediatric solid tumor that is often driven by oncogenic mutations or rearrangements of the gene encoding the tyrosine kinase receptor ALK. In relapsed neuroblastoma, the frequency of ALK mutation is increased, highlighting the importance of understanding ALK signaling in this cancer. Two papers identify alternative targets in ALK-driven neuroblastoma cells. By combining various proteomics analyses with protein-protein interaction networks, Emdal et al. found that IRS2, an adaptor protein in the insulin receptor signaling pathway, linked ALK signaling to neuroblastoma cell survival. Van den Eynden et al. integrated proteomics and gene expression analyses to identify ETS family transcription factors and the MAPK phosphatase DUSP4 as targets of ALK signaling. These papers identify new targets that could be exploited to treat ALK-positive neuroblastoma.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154048 (URN)10.1126/scisignal.aar5680 (DOI)000451217900004 ()30459281 (PubMedID)
Funder
Swedish Cancer Society, BH CAN15/775Swedish Cancer Society, RHP CAN15/391Swedish Cancer Society, EL CAN15/541Swedish Childhood Cancer Foundation, BH 2015-80Swedish Childhood Cancer Foundation, BH 2014-150Swedish Childhood Cancer Foundation, RHP 2015-96Swedish Childhood Cancer Foundation, JG TJ2016-0088Swedish Childhood Cancer Foundation, PR2016-2011Swedish Research Council, RHP 2015-04466Swedish Research Council, BH 2017-01324Swedish Research Council, EL 14-3596Swedish Foundation for Strategic Research , RB13-0204Göran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg Foundation, KAW 2015.0144EU, Horizon 2020, 675712
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Guan, J., Yamazaki, Y., Chand, D., van Dijk, J. R., Ruuth, K., Palmer, R. H. & Hallberg, B. (2017). Novel mechanisms of ALK activation revealed by analysis of the Y1278S neuroblastoma mutation. Cancers, 9(11), Article ID 149.
Open this publication in new window or tab >>Novel mechanisms of ALK activation revealed by analysis of the Y1278S neuroblastoma mutation
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2017 (English)In: Cancers, ISSN 2072-6694, Vol. 9, no 11, article id 149Article in journal (Refereed) Published
Abstract [en]

Numerous mutations have been observed in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) in both germline and sporadic neuroblastoma. Here, we have investigated the Y1278S mutation, observed in four patient cases, and its potential importance in the activation of the full length ALK receptor. Y1278S is located in the 1278-YRASYY-1283 motif of the ALK activation loop, which has previously been reported to be important in the activation of the ALK kinase domain. In this study, we have characterized activation loop mutations within the context of the full length ALK employing cell culture and Drosophila melanogaster model systems. Our results show that the Y1278S mutant observed in patients with neuroblastoma harbors gain-of-function activity. Secondly, we show that the suggested interaction between Y1278 and other amino acids might be of less importance in the activation process of the ALK kinase than previously proposed. Thirdly, of the three individual tyrosines in the 1278-YRASYY-1283 activation loop, we find that Y1283 is the critical tyrosine in the activation process. Taken together, our observations employing different model systems reveal new mechanistic insights on how the full length ALK receptor is activated and highlight differences with earlier described activation mechanisms observed in the NPM-ALK fusion protein, supporting a mechanism of activation more in line with those observed for the Insulin Receptor (InR).

Place, publisher, year, edition, pages
MDPI, 2017
Keywords
ALK, kinase activation, activation loop, gain-of-function, mutation analyses, Insulin receptor, NPM-ALK, oncogene, neuroblastoma
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-106700 (URN)10.3390/cancers9110149 (DOI)000416603300005 ()
Note

Originally included in thesis in manuscript form.

Available from: 2015-08-11 Created: 2015-08-03 Last updated: 2018-06-07Bibliographically approved
Guan, J., Tucker, E. R., Wan, H., Chand, D., Danielson, L. S., Ruuth, K., . . . Hallberg, B. (2016). The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. Disease Models and Mechanisms, 9(9), 941-952
Open this publication in new window or tab >>The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN
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2016 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 9, p. 941-952Article in journal (Refereed) Published
Abstract [en]

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-128479 (URN)10.1242/dmm.024448 (DOI)000387578200004 ()27483357 (PubMedID)
Available from: 2016-12-15 Created: 2016-12-05 Last updated: 2018-06-09Bibliographically approved
Amer, A., Gurung, J., Costa, T., Ruuth, K., Zavialov, A., Forsberg, Å. & Francis, M. S. (2016). YopN and TyeA Hydrophobic Contacts Required for Regulating Ysc-Yop Type III Secretion Activity by Yersinia pseudotuberculosis. Frontiers in Cellular and Infection Microbiology, 6, Article ID 66.
Open this publication in new window or tab >>YopN and TyeA Hydrophobic Contacts Required for Regulating Ysc-Yop Type III Secretion Activity by Yersinia pseudotuberculosis
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2016 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 6, article id 66Article in journal (Refereed) Published
Abstract [en]

Yersinia bacteria target Yop effector toxins to the interior of host immune cells by the Ysc-Yop type III secretion system. A YopN-TyeA heterodimer is central to controlling Ysc-Yop targeting activity. A + 1 frameshift event in the 3-prime end of yopN can also produce a singular secreted YopN-TyeA polypeptide that retains some regulatory function even though the C-terminal coding sequence of this YopN differs greatly from wild type. Thus, this YopN C-terminal segment was analyzed for its role in type III secretion control. Bacteria producing YopN truncated after residue 278, or with altered sequence between residues 279 and 287, had lost type III secretion control and function. In contrast, YopN variants with manipulated sequence beyond residue 287 maintained full control and function. Scrutiny of the YopN-TyeA complex structure revealed that residue W279 functioned as a likely hydrophobic contact site with TyeA. Indeed, a YopNW279G mutant lost all ability to bind TyeA. The TyeA residue F8 was also critical for reciprocal YopN binding. Thus, we conclude that specific hydrophobic contacts between opposing YopN and TyeA termini establishes a complex needed for regulating Ysc-Yop activity.

Keywords
protein-protein interaction, molecular modelling, protein secretion, mutagenesis, bacterial pathogenesis, regulation
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-122904 (URN)10.3389/fcimb.2016.00066 (DOI)000378543500001 ()
Funder
Swedish Research Council
Available from: 2016-06-23 Created: 2016-06-23 Last updated: 2018-06-07Bibliographically approved
Fransson, S., Hansson, M., Ruuth, K., Djos, A., Berbegall, A., Javanmardi, N., . . . Martinsson, T. (2015). Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors. Genes, Chromosomes and Cancer, 54(2), 99-109
Open this publication in new window or tab >>Intragenic Anaplastic Lymphoma Kinase (ALK) Rearrangements: Translocations as a Novel Mechanism of ALK Activation in Neuroblastoma Tumors
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2015 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 2, p. 99-109Article in journal (Refereed) Published
Abstract [en]

Anaplastic lymphoma kinase (ALK) has been demonstrated to be deregulated in sporadic as well as in familiar cases of neuroblastoma (NB). Whereas ALK-fusion proteins are common in lymphoma and lung cancer, there are few reports of ALK rearrangements in NB indicating that ALK mainly exerts its oncogenic capacity via activating mutations and/or overexpression in this tumor type. In this study, 332 NB tumors and 13 cell lines were screened by high resolution single nucleotide polymorphism microarray. Gain of 2p was detected in 23% (60/332) of primary tumors and 46% (6/13) of cell lines, while breakpoints at the ALK locus were detected in four primary tumors and two cell lines. These were further analyzed by next generation sequencing and a targeted enrichment approach. Samples with both ALK and MYCN amplification displayed complex genomic rearrangements with multiple breakpoints within the amplicon. None of the translocations characterized in primary NB tumors are likely to result in a chimeric protein. However, immunohistochemical analysis reveals high levels of phosphorylated ALK in these samples despite lack of initial exons, possibly due to alternative transcription initiation sites. Both ALK proteins predicted to arise from such alterations and from the abnormal ALK exon 4-11 deletion observed in the CLB-BAR cell line show strong activation of downstream targets STAT3 and extracellular signal-regulated kinase (ERK) when expressed in PC12 cells. Taken together, our data indicate a novel, although rare, mechanism of ALK activation with implications for NB tumorigenesis. 

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-99211 (URN)10.1002/gcc.22223 (DOI)000346348600005 ()
Available from: 2015-04-22 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved
Umapathy, G., El Wakil, A., Witek, B., Chesler, L., Danielson, L., Deng, X., . . . Hallberg, B. (2014). The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Science Signaling, 7(349), ra102
Open this publication in new window or tab >>The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma
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2014 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, ISSN 1945-0877 (print), Vol. 7, no 349, p. ra102-Article in journal (Refereed) Published
Abstract [en]

Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.

Place, publisher, year, edition, pages
American association for the Advancement of Science, 2014
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-96953 (URN)10.1126/scisignal.2005470 (DOI)000344145900003 ()
Available from: 2015-02-24 Created: 2014-12-05 Last updated: 2018-06-07Bibliographically approved
Chand, D., Yamazaki, Y., Ruuth, K., Schönherr, C., Martinsson, T., Kogner, P., . . . Hallberg, B. (2013). Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. Disease Models and Mechanisms, 6(2), 373-382
Open this publication in new window or tab >>Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma
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2013 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 2, p. 373-382Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma is a childhood extracranial solid tumor which is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly required characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and 1464STOP) which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression we have employed cell culture based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position F1174I generates a gain-of-function receptor capable of activating intracellular targets, such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These are: (i) gain-of-function ligand independent mutations such as ALK(F1174), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T)(Schonherr et al 2011a) or (iii) ALK mutations which are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (PF-02341066, Xalkori), albeit with differing levels of sensitivity.

Place, publisher, year, edition, pages
Cambridge, UK: The Company of Biologists Ltd, 2013
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-61265 (URN)10.1242/dmm.010348 (DOI)000317266500009 ()23104988 (PubMedID)
Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2018-06-08Bibliographically approved
Sattu, K., Hochgräfe, F., Wu, J., Umapathy, G., Schönherr, C., Ruuth, K., . . . Hallberg, B. (2013). Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells. Paper presented at 6th Garvan Signalling Symposium, 2012. The FEBS Journal, 280(21), 5269-5282
Open this publication in new window or tab >>Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells
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2013 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 280, no 21, p. 5269-5282Article in journal (Refereed) Published
Abstract [en]

Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin-ALK and echinoderm microtubule-associated protein-like 4-ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
Keywords
anaplastic lymphoma kinase, cancer, neuroblastoma, SHP-2, signal transducer and activator of transcription 3 (STAT3)
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-81092 (URN)10.1111/febs.12453 (DOI)000328622200027 ()23889739 (PubMedID)
Conference
6th Garvan Signalling Symposium, 2012
Funder
Swedish Cancer Society, 12-0722, 120796Swedish Research Council, 621-2011-5181, 521-2012-2831
Note

Special Issue: Frontiers in Cell Signalling, and Ca2+-Signalling and Transport in Health and Disease

Available from: 2013-10-02 Created: 2013-10-02 Last updated: 2018-06-08Bibliographically approved
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