title: Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions.
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.
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Reshetnyak
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Murray
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Xiarong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Mo
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Jyotidarsini
authors.initials: J
authors.lastname: Mohanty
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Francisco
authors.initials: F
authors.lastname: Tome
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06520.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520;
authors.forename: Irit
authors.initials: I
authors.lastname: Lax
authors.affiliation: Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Joseph.Schlessinger@Yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
mesh_terms: D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: C000609778:ALKAL1 protein, human; C000609777:ALKAL2 protein, human; D016207:Cytokines; D008024:Ligands; D006493:Heparin; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; C489300:LTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D004318:Doxycycline
keywords: cancer; cell signaling; phosphorylation; protein kinases; surface receptors