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The constitutive ac...
The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking
- Article/chapterEnglish2011
Publisher, publication year, extent ...
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2011-01-17
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Springer Science and Business Media LLC,2011
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:umu-43275
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-43275URI
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https://doi.org/10.1038/onc.2010.595DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N-linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors.Oncogene advance online publication, 17 January 2011; doi:10.1038/onc.2010.595.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Cazes, A
(author)
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Boutterin, M C
(author)
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Figueiredo, A
(author)
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Raynal, V
(author)
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Combaret, V
(author)
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Hallberg, BengtUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Hallberg(Swepub:umu)beha0004
(author)
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Palmer, Ruth HUmeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)(Swepub:umu)rupa0001
(author)
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Delattre, O
(author)
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Janoueix-Lerosey, I
(author)
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Vigny, M
(author)
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Umeå universitetInstitutionen för molekylärbiologi (Medicinska fakulteten)
(creator_code:org_t)
Related titles
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In:Oncogene: Springer Science and Business Media LLC30, s. 2017-20250950-92321476-5594
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Oncogene
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Mazot, P
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Cazes, A
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Boutterin, M C
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Figueiredo, A
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Raynal, V
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Combaret, V
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Hallberg, Bengt
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Palmer, Ruth H
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Delattre, O
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Janoueix-Lerosey ...
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Vigny, M
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- NATURAL SCIENCES
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NATURAL SCIENCES
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Oncogene
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Umeå University