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FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase
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2015 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 4, article id e09811Article in journal (Refereed) Published
Abstract [en]

Aberrant activation of anaplastic lymphoma kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer, 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild-type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor.

Place, publisher, year, edition, pages
Cambridge: eLife Sciences Publications , 2015. Vol. 4, article id e09811
Keywords [en]
ALK, Anaplastic lymphoma kinase, D. melanogaster, FAM150, LTK, cell biology, human, ligand, neuroblastoma, signaling
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-163391DOI: 10.7554/eLife.09811ISI: 000373879300001PubMedID: 26418745OAI: oai:DiVA.org:umu-163391DiVA, id: diva2:1352273
Available from: 2019-09-18 Created: 2019-09-18 Last updated: 2019-09-18Bibliographically approved
In thesis
1. Harnessing the power of model systems to investigate regulation of Anaplastic Lymphoma Kinase function
Open this publication in new window or tab >>Harnessing the power of model systems to investigate regulation of Anaplastic Lymphoma Kinase function
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The anaplastic lymphoma kinase (ALK), initially identified as a translocation partner in anaplastic large cell lymphoma (ALCL), has been described in a number of tumors such as neuroblastoma. Neuroblastoma is a neural crest derived malignancy of the sympathetic nervous system. Therefore, understanding regulation of ALK transcription and activity in the context of normal neural crest development might highlight abnormal events contributing to neuroblastoma initiation. The use of vertebrate model systems has been very important for studying in detail the pathways activated during neural crest development, their contribution to neuroblastoma and the identification of therapeutic targets.

Using a yeast one-hybrid approach, we identified Odd-paired (Opa) as a potential transcription factor modulating Alk expression in the Drosophila visceral mesoderm (VM) (Paper I). Opa promotes Alk expression in the VM in combination with Bagpipe (Bap) and Biniou (Bin) through binding to the here identified AlkEB9 enhancer region.

In a subsequent paper, we identified ALKAL1 and ALKAL2 as the activating ligands for the human ALK (Paper II). Using a combination of in vitro and cell culture assays we show that the ALKAL proteins can bind and activate human ALK. Moreover, ALKAL proteins can “super-activate” mutant ALK, highlighting a putative role for the ALKALs/ALK axis in neuroblastoma.

The third paper shows in vivo evidence of ALKAL activity during zebrafish neural crest development (Paper III). We identified and characterized three zebrafish Alkal proteins and demonstrated their ability to activate human and zebrafish ALK family RTKs. Zebrafish Alkals activate the ALK-related receptor leukocyte tyrosine kinase (LTK) in the neural crest to promote iridophore development.

In the last paper, we employed the DamID approach on the Drosophila VM and identified the transcription factor Kahuli (Kah) as an Alk transcriptional target in this tissue (Paper IV). We also addressed the in vivo iv Kah role during embryogenesis and showed that Kah is required for normal midgut invaginations and formation of the body wall musculature.

Together, this thesis highlights the importance of ALK receptor signaling during development in vertebrate and invertebrate models. Further, it shows that ALKAL signaling via the activation of the ALK family receptors are involved in neural crest development.

Place, publisher, year, edition, pages
Umea: Academic Publications, 2019. p. 69
Keywords
RTK, ALK, Drosophila, Danio rerio, ALKALs, signal transduction, transcription factor, visceral mesoderm, iridophores, neural crest
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-163395 (URN)978-91-7855-095-1 (ISBN)
Public defence
2019-10-11, Europa hörsalen, Conference Center Wallenberg, Medicinaregatan 20, Gothenburg, 13:00 (English)
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I publikationen felaktigt angivet att avhandlingen ingår i serien Umeå University medical dissertations, ISSN 0346-6612. 

Available from: 2019-09-20 Created: 2019-09-18 Last updated: 2019-09-24Bibliographically approved

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