MOLECULAR CHARACTERIZATION AND CHROMOSOMAL LOCALIZATION OF DRT (EPHT3) - A DEVELOPMENTALLY-REGULATED HUMAN PROTEIN-TYROSINE KINASE GENE OF THE EPH FAMILY

By screening a human fetal brain cDNA expression library using a monoc lonal antiphosphotyrosine antibody and by 5' RACE procedures, we have isolated overlapping cDNAs encoding a receptor-type tyrosine kinase be longing to the EPH family, DRT (Developmentally Regulated EPH-related Tyrosine kinase gene). The DRT gene is expressed in three different si ze transcripts (i.e. 4, 5 and 11 kb). DRT transcripts are expressed in human brain and several other tissues, including heart, lung, kidney, placenta, pancreas, liver and skeletal muscle, but the 11 kb DRT tran script is preferentially expressed in fetal brain. Steady-state levels of DRT mRNA in several tissues, including brain, heart, lung and kidn ey, are greater in the midterm fetus than those in the adult. DRT tran scripts are detectable at low levels in a human teratocarcinoma cell l ine (N Tera-2), but its expression is greatly increased after the NTer a-2 cells are induced to become postmitotic neurons (NTera-2N) by reti noic acid treatment. These data suggest that DRT plays a part in human neurogenesis. A large number of tumor cell lines derived from neuroec toderm express DRT transcripts, including 12 neuroblastomas, two medul loblastomas, one primitive neuroectodermal tumor and six small cell lu ng carcinomas (SCLC). Interestingly, several neuroblastoma cell lines with lp deletion and one SCLC cell line express DRT transcripts of abe rrant size (i.e. 3, 6 and 8 kb) in addition to those found in normal t issues. We mapped the DRT gene to human chromosome 1p35-1p36.1 by PCR screening of human-rodent somatic cell hybrid panels and by fluorescen ce in situ hybridization. As the distal end of chromosome 1p is often deleted in neuroblastomas and altered in some cases in SCLCs, these ch romosomal abnormalities may have resulted in the generation of aberran t size transcripts. Thus, the DRT gene may play a part in neuroblastom a and SCLC tumorigenesis.