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ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells.

Journal article
Authors Andrey Fadeev
Patricia Mendoza-García
Uwe Irion
Jikui Guan
Kathrin Pfeifer
Stephanie Wiessner
Fabrizio Serluca
Ajeet Pratap Singh
Christiane Nüsslein-Volhard
Ruth H. Palmer
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 115
Issue 4
Pages E630-E638
ISSN 1091-6490
Publication year 2018
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages E630-E638
Language en
Subject categories Biological Sciences, Cell and Molecular Biology


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.

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