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Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk.

ABSTRACT: Anaplastic lymphoma kinase (Alk) and leucocyte tyrosine kinase (Ltk) were identified as "orphan" receptor tyrosine kinases (RTKs) with oncogenic potential. Recently ALKAL1 and ALKAL2 (also named "augmentor-?" and "augmentor-?" or "FAM150A" and "FAM150B," respectively) were discovered as physiological ligands of Alk and Ltk. Here, we employ zebrafish as a model system to explore the physiological function and to characterize in vivo links between Alk and Ltk with their ligands. Unlike the two ligands encoded by mammalian genomes, the zebrafish genome contains three genes: aug-?1, aug-?2, and aug-? Our experiments demonstrate that these ligands play an important role in zebrafish pigment development. Deficiency in aug-?1, aug-?2, and aug-? results in strong impairment in iridophore patterning of embryonic and adult zebrafish that is phenocopied in zebrafish deficient in Ltk. We show that aug-?1 and aug-?2 are essential for embryonic iridophore development and adult body coloration. In contrast, aug-?2 and aug-? are essential for iridophore formation in the adult eye. Importantly, these processes are entirely mediated by Ltk and not by Alk. These experiments establish a physiological link between augmentor ligands and Ltk and demonstrate that particular augmentors activate Ltk in a tissue-specific context to induce iridophore differentiation from neural crest-derived cells and pigment progenitor cells.

SUBMITTER: Mo ES

PROVIDER: S-EPMC5692561 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk.

Mo Elizabeth S ES Cheng Qianni Q Reshetnyak Andrey V AV Schlessinger Joseph J Nicoli Stefania S

Proceedings of the National Academy of Sciences of the United States of America 20171023 45

Anaplastic lymphoma kinase (Alk) and leucocyte tyrosine kinase (Ltk) were identified as "orphan" receptor tyrosine kinases (RTKs) with oncogenic potential. Recently ALKAL1 and ALKAL2 (also named "augmentor-β" and "augmentor-α" or "FAM150A" and "FAM150B," respectively) were discovered as physiological ligands of Alk and Ltk. Here, we employ zebrafish as a model system to explore the physiological function and to characterize in vivo links between Alk and Ltk with their ligands. Unlike the two lig ...[more]

PMID: 29078341

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Project description:IntroductionThis study explored the use, safety, and efficacy of initial use of an ALK-inhibiting targeted therapy (ALK tyrosine kinase inhibitor [TKI]) in patients with ALK-rearranged NSCLC in a population-based, real-world clinical population within the province of Alberta, Canada.MethodsDemographic, clinical, treatment, and outcome data of the patients with advanced or metastatic ALK-rearranged NSCLC receiving their first ALK TKI between 2014 and 2019 were included in the analysis.ResultsA total of 92 patients with ALK-rearranged NSCLC treated with ALK TKI (78% crizotinib, 22% alectinib) were identified. In the ALK-rearranged cohort, 1-year survival rate was 73% and median overall survival (OS) and progression-free survival (PFS) were 48.5 months and 17.0 months, respectively. An objective response rate of 49% was observed, and adverse events were reported in 70% of the patients, primarily of low grade (84%). Case-matched comparison to patients with ALK-wildtype disease treated with cytotoxic chemotherapy revealed the benefit of ALK TKI in the context of an ALK rearrangement (ALK-rearranged versus ALK-wildtype) (median post-treatment initiation OS: 46.8 versus 14.2 mo, p < 0.001). Outcomes, measured from the time of ALK TKI initiation, differed by Eastern Cooperative Oncology Group (ECOG) (ECOG < 2 versus ECOG ≥ 2) (median OS: not reached versus 6.8 mo, p < 0.001; median PFS 17.6 versus 7.4 mo, p = 0.02), disease presentation (relapsed versus de novo) (median PFS: 30.8 versus 15.0 mo, p = 0.04), and brain metastasis onset (brain metastases development during ALK TKI versus baseline brain metastases) (not reached versus 12.8 mo, p = 0.04).ConclusionsClinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer.

Dataset Information

Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk.

Publications

Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk.

Similar Datasets

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