FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase

Abstract

Aberrant activation of anaplastic lymphoma kinase (ALK) has been described in a range of human cancers, including non-small cell lung cancer and neuroblastoma (Hallberg and Palmer, 2013). Vertebrate ALK has been considered to be an orphan receptor and the identity of the ALK ligand(s) is a critical issue. Here we show that FAM150A and FAM150B are potent ligands for human ALK that bind to the extracellular domain of ALK and in addition to activation of wild-type ALK are able to drive 'superactivation' of activated ALK mutants from neuroblastoma. In conclusion, our data show that ALK is robustly activated by the FAM150A/B ligands and provide an opportunity to develop ALK-targeted therapies in situations where ALK is overexpressed/activated or mutated in the context of the full length receptor.DOI: http://dx.doi.org/10.7554/eLife.09811.001

Adult systemic anaplastic large-cell lymphoma: recommendations for diagnosis and management

“…ALK protein is absent in normal human tissues but is expressed in embryonal neuronal tissues, and is believed to have a critical role in normal neuronal embryogenesis. The ligand to its receptor remains unknown in mammals, though recently heparin [35] and FAM150A and FAM150B [36] were reported as possible activating ligands for ALK kinase.…”

Adopting ALK and LTK

“…Guan et al (13) also coexpressed human ALK with either FAM150A or FAM150B in vivo, in the developing Drosophila eye. Expression of FAM150A, FAM150B, or human (wild-type) ALK alone yielded no perturbation of fly eye development, but expression of either FAM150A or FAM150B together with human ALK resulted in a rough eye phenotype (13). Again, however, the expression levels of the ligands and the receptors were uncontrolled, and it is possible that these levels were anomalously high.…”

“…Although there is still work to be done, the studies of Zhang et al (12), Guan et al (13), and Reshetnyak et al (5) unambiguously position AUG-α/β (FAM150B/A) as protein ligands for the ALK/LTK family. These analyses reflect the closing of an era, in that we can soon look forward to the day when the RTK orphanage is finally shuttered.…”

Genome-wide association study of clinical parameters in immunoglobulin light chain amyloidosis in three patient cohorts

“…Iman Meziane, 1 10 Anna Jauch, 11 Gareth J. Morgan, 3 Richard Houlston, 9,10 Hartmut Goldschmidt, 2,12 Paolo Milani, 13,14 Giampaolo Merlini, 13,14 …”

“…These belong to the insulin receptor superfamily, and their aberrant activation has been described in many cancers, such as non-small lung cancer and neuroblastoma in which ALK mutations are common. 9 Fusion genes of ALK are often found in lymphomas with resulting downstream activation of the Ras/Raf/MEK/ERK pathway.…”