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Harnessing the power of model systems to investigate regulation of Anaplastic Lymphoma Kinase function
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). University of Gothenburg. (Ruth Palmer)ORCID-id: 0000-0002-6084-7962
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umea: Academic Publications, 2019. , s. 69
Nyckelord [en]
RTK, ALK, Drosophila, Danio rerio, ALKALs, signal transduction, transcription factor, visceral mesoderm, iridophores, neural crest
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-163395ISBN: 978-91-7855-095-1 (tryckt)OAI: oai:DiVA.org:umu-163395DiVA, id: diva2:1352332
Disputation
2019-10-11, Europa hörsalen, Conference Center Wallenberg, Medicinaregatan 20, Gothenburg, 13:00 (Engelska)
Opponent
Handledare
Anmärkning

I publikationen felaktigt angivet att avhandlingen ingår i serien Umeå University medical dissertations, ISSN 0346-6612. 

Tillgänglig från: 2019-09-20 Skapad: 2019-09-18 Senast uppdaterad: 2019-09-24Bibliografiskt granskad
Delarbeten
1. The Zic family homologue Odd-paired regulates Alk expression in Drosophila
Öppna denna publikation i ny flik eller fönster >>The Zic family homologue Odd-paired regulates Alk expression in Drosophila
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2017 (Engelska)Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 4, artikel-id e1006617Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.

Ort, förlag, år, upplaga, sidor
PUBLIC LIBRARY SCIENCE, 2017
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-137009 (URN)10.1371/journal.pgen.1006617 (DOI)000402549200004 ()
Tillgänglig från: 2017-06-29 Skapad: 2017-06-29 Senast uppdaterad: 2019-09-18Bibliografiskt granskad
2. FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase
Öppna denna publikation i ny flik eller fönster >>FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase
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2015 (Engelska)Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 4, artikel-id e09811Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Cambridge: eLife Sciences Publications, 2015
Nyckelord
ALK, Anaplastic lymphoma kinase, D. melanogaster, FAM150, LTK, cell biology, human, ligand, neuroblastoma, signaling
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-163391 (URN)10.7554/eLife.09811 (DOI)000373879300001 ()26418745 (PubMedID)
Tillgänglig från: 2019-09-18 Skapad: 2019-09-18 Senast uppdaterad: 2019-09-18Bibliografiskt granskad
3. ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells
Öppna denna publikation i ny flik eller fönster >>ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells
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2018 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 4, s. E630-E638Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
National Academy of Sciences, 2018
Nyckelord
ALK, ALKAL, FAM150, Ltk, iridophore
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-144835 (URN)10.1073/pnas.1719137115 (DOI)000423097800012 ()29317532 (PubMedID)
Tillgänglig från: 2018-03-02 Skapad: 2018-03-02 Senast uppdaterad: 2019-09-18Bibliografiskt granskad
4. DamID transcriptional profiling identifies Kahuli as a downstream target of Alk
Öppna denna publikation i ny flik eller fönster >>DamID transcriptional profiling identifies Kahuli as a downstream target of Alk
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-163397 (URN)
Tillgänglig från: 2019-09-18 Skapad: 2019-09-18 Senast uppdaterad: 2019-09-18

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