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Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15862-7. doi: 10.1073/pnas.1520099112. Epub 2015 Nov 16.

Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions.

Author information

1
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
2
Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520.
3
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Joseph.Schlessinger@Yale.edu.

Abstract

Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-α (AUG-α), as a ligand for ALK. AUG-α binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-α binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-β) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-α stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states.

KEYWORDS:

cancer; cell signaling; phosphorylation; protein kinases; surface receptors

Comment in

PMID:
26630010
PMCID:
PMC4702955
DOI:
10.1073/pnas.1520099112
[Indexed for MEDLINE]
Free PMC Article

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