Adopting ALK and LTK.

RTKs and Their Ligands Aberrant, uncontrolled activation of receptor tyrosine kinases (RTKs) is the “original sin” of many human cancers, in that this activation can both initiate and drive the evolution of tumors (1). Mutation and overexpression of the multiple members of the epidermal growth factor/ErbB receptor family, to cite only a single example, constitute cancer drivers that have been clinically targeted by a panoply of biologic and small-molecule inhibitors for more than a decade (2, 3). Given the consequences of their activation, RTKs are always tightly regulated: their steady-state enzymatic (tyrosine kinase) activity is very low in the absence of activation, which is normally triggered by the binding of a protein ligand to the RTK extracellular domain (4). This aspect has made the identification of RTK ligands an especially important goal, and studies over the last three decades have uncovered the ligands for nearly all of the 58 RTKs encoded in the human genome. Two closely related RTKs— the anaplastic lymphoma kinase (ALK) and the leukocyte tyrosine kinase (LTK)—have been notable holdouts, in that they have remained receptor “orphans” without a ligand. This is no longer the case. In PNAS, Reshetnyak et al. (5) identify “family with sequence similarity” (FAM) 150A and 150B— rechristened augmentor-β and augmentor-α, respectively, by the authors—as protein ligands for ALK and LTK. These two RTKs share distinctive structural features, including highly conserved tyrosine kinase domains and unusual glycine-rich regions in their ligand-binding extracellular domains (ectodomains) that exhibit 55% amino acid identity between the receptors. ALK has been very widely studied in cancer (6), particularly in nonsmall-cell lung carcinoma, neuroblastoma, and anaplastic largecell lymphoma, with which it was first associated (7). ALK-driven cancers have been seen to arise from gene fusion events between the ALK kinase domain and various protein-coding domains, by mutations in fulllength ALK, or via overexpression of the ALK protein. Crizotinib, ceritinib, and other smallmolecule ALK inhibitors are now used as therapies for nonsmall-cell lung carcinoma (8). This clinical activity notwithstanding, the biological roles that ALK plays in either vertebrate development or mature physiology are not well understood. ALK knockout mice do not display strong phenotypes, although defects in mature brain (cortical and hippocampal) function have been reported (9). LTK is murkier still: experiments in zebrafish