期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：15741-15745
DOI：10.1073/pnas.1412009111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceSecreted factors and their cell-surface receptors play important roles in the communication between cells in normal and pathological conditions. There are many transmembrane receptor-like proteins whose ligands have not been identified (also known as orphan receptors). Knowledge of the ligand should help in understanding the biological role of the receptor. We used a strategy of screening the extracellular proteome, one protein at a time, to identify ligands for such receptors. We discovered the ligands for the orphan receptor leukocyte tyrosine kinase. To our knowledge, this is the first case in which secreted factor ligands were identified for an orphan receptor with this technique. This approach is especially valuable when little is known about the ligand. There are many transmembrane receptor-like proteins whose ligands have not been identified. A strategy for finding ligands when little is known about their tissue source is to screen each extracellular protein individually expressed in an array format by using a sensitive functional readout. Taking this approach, we have screened a large collection (3,191 proteins) of extracellular proteins for their ability to activate signaling of an orphan receptor, leukocyte tyrosine kinase (LTK). Only two related secreted factors, FAM150A and FAM150B (family with sequence similarity 150 member A and member B), stimulated LTK phosphorylation. FAM150A binds LTK extracellular domain with high affinity (KD = 28 pM). FAM150A stimulates LTK phosphorylation in a ligand-dependent manner. This strategy provides an efficient approach for identifying functional ligands for other orphan receptors.
