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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, eLife digest Cells have receptor proteins on their surface that enable them to detect changes in their environment and communicate with other cells. Signal molecules bind to a segment of the receptor called the extracellular domain that faces out from the cell. This can result in the activation of another domain in the receptor that is just inside the cell, which, in turn, activates signaling pathways that relay the information around the cell. However, these communication systems are often disrupted in cancer cells. This helps the cells to override the strict growth controls imposed upon them by other (healthy) cells in the body. The gene that encodes a receptor protein called Anaplastic Lymphoma Kinase (or ALK for short) is often mutated in some types of human cancer so that the protein is always active. However, we still do not know what signal molecules bind to the ALK protein to activate it in normal cells. Guan, Umapathy et al. used a variety of cell biology and biochemical techniques to study the role of ALK. The experiments show that when either of two proteins called FAM150A and FAM150B are produced in rat nerve cells alongside ALK, the nerve cells rapidly respond and form outgrowths. Experiments using cancer cells derived from human nerve cells also yielded similar results. Guan, Umapathy et al. found that the extracellular domain of ALK can physically interact with FAM150A and FAM150B. The eyes of fruit flies that had been genetically modified to produce the human ALK protein alongside either FAM150A or FAM150B grew more than normal, giving the eyes an abnormal "rough" appearance. Further experiments showed that FAM150A and FAM150B are also able to increase the level of activation of an ALK mutant protein that is already active. Therefore, in future, the development of drugs that stop FAM150A and FAM150B from binding to ALK may be useful for treating cancers that are driven by high levels of ALK activity. Many challenging questions lie ahead to better understand how FAM150A and FAM150B interact with ALK. DOI: http://dx.doi.org/10.7554/eLife.09811.002

Genes regulating Caenorhabditis elegans insulin/IGF signaling (IIS) have largely been identified on the basis of their involvement in dauer development or longevity. A third IIS phenotype is the first larval stage (L1) diapause, which is also influenced by asna-1, a regulator of DAF-28/insulin secretion. We reasoned that new regulators of IIS strength might be identified in screens based on the L1 diapause and the asna-1 phenotype. Eighty- six genes were selected for analysis by virtue of their predicted interaction with ASNA-1 and screened for asna-1-like larval arrest. ykt-6, mrps-2, mrps-10 and mrpl-43 were identified as genes which, when inactivated, caused larval arrest without any associated feeding defects. Several tests indicated that IIS strength was weaker and that insulin secretion was defective in these animals. This study highlights the role of the Golgi network and the mitochondria in insulin secretion and provides a new list of genes that modulate IIS in C. elegans.