Change search
ReferencesLink to record
Permanent link

Direct link
The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking
Show others and affiliations
2011 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 30, 2017-2025 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 30, 2017-2025 p.
Keyword [en]
ALK, neuroblastoma, phosphorylation, ER retention, RTK
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-43275DOI: 10.1038/onc.2010.595PubMedID: 21242967OAI: diva2:412721
Available from: 2011-04-26 Created: 2011-04-26 Last updated: 2012-09-04Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Hallberg, BengtPalmer, Ruth H
By organisation
Department of Molecular Biology (Faculty of Medicine)Department of Molecular Biology (Faculty of Science and Technology)
In the same journal
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 93 hits
ReferencesLink to record
Permanent link

Direct link