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ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 4, p. E630-E638Article in journal (Refereed) Published
Abstract [en]

Mutations in anaplastic lymphoma kinase (ALK) are implicated in somatic and familial neuroblastoma, a pediatric tumor of neural crest-derived tissues. Recently, biochemical analyses have identified secreted small ALKAL proteins (FAM150, AUG) as potential ligands for human ALK and the related leukocyte tyrosine kinase (LTK). In the zebrafish Danio rerio, DrLtk, which is similar to human ALK in sequence and domain structure, controls the development of iridophores, neural crest-derived pigment cells. Hence, the zebrafish system allows studying Alk/Ltk and Alkals involvement in neural crest regulation in vivo. Using zebrafish pigment pattern formation, Drosophila eye patterning, and cell culture-based assays, we show that zebrafish Alkals potently activate zebrafish Ltk and human ALK driving downstream signaling events. Overexpression of the three DrAlkals cause ectopic iridophore development, whereas loss-of-function alleles lead to spatially distinct patterns of iridophore loss in zebrafish larvae and adults. alkal loss-of-function triple mutants completely lack iridophores and are larval lethal as is the case for ltk null mutants. Our results provide in vivo evidence of (i) activation of ALK/LTK family receptors by ALKALs and (ii) an involvement of these ligand-receptor complexes in neural crest development.

Place, publisher, year, edition, pages
National Academy of Sciences , 2018. Vol. 115, no 4, p. E630-E638
Keywords [en]
ALK, ALKAL, FAM150, Ltk, iridophore
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-144835DOI: 10.1073/pnas.1719137115ISI: 000423097800012PubMedID: 29317532OAI: oai:DiVA.org:umu-144835DiVA, id: diva2:1187075
Available from: 2018-03-02 Created: 2018-03-02 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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Supervisors
Note

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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Mendoza-Garcia, Patricia

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