Hek and elk are members of the eph-related family of receptor tyrosine kinases. Recently, we isolated five cDNAs encoding membrane-bound ligands to hek and elk. Because of the promiscuous nature of their binding, we have termed these proteins ligands of the eph-related kinases or LERKs. The LERKs can be divided into two subgroups by virtue of their sequence identity, binding properties, and mode of cell membrane attachment. For example, LERK-2 (EPLG2, Epl2) and LERK-5 (EPLG5, Epl5) are type 1 transmembrane proteins, while LERK-1 (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are anchored to the membrane by glycosyl-phosphatidylinositol (GPI) linkage. Using Southern hybridization analysis of human x rodent somatic cell hybrid DNAs, we have assigned the genes that encode the GPI-anchored LERKs (EPLG1, EPLG3, and EPLG4) to human chromosome 1. Fluorescence in situ hybridization to metaphase chromosome preparations using genomic clones from each locus refined this localization to chromosome 1, bands q21-q22. In addition, Southern blot analysis of DNA from interspecific backcross mice indicated that the mouse homologues Epl1, Epl3, and Epl4 map to a homologous region on mouse chromosome 3.