A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28 gastric cancer cells

We have isolated a gene from stomach fibroblasts encoding novel proteins co ntaining two follistatin modules which might bind TGF-beta-related growth f actors and a single epidermal growth factor (EGF)-like domain which is clos ely related to EGF/Neuregulin (NRG) family growth factors. Sequence analysi s revealed novel cDNA clones, the protein products of which were designated tomoregulin (TR) and consisted of at least three isoforms which were disti nguished by their cytoplasmic domains. The cytoplasmic domains in all isofo rms were short and contained potential G-protein activating motifs. Precurs ors of TR (Pro-TR) are glycosylated transmembrane proteins. Two secreted so luble forms resulting from proteolytic cleavage were distinguished by the p resence or absence of the EGF-like domain. The EGF-like domain of TR was hi ghly conserved compared to EGF/NRG family growth factors with the exception of an arginine to histidine substitution at position 39 (Arg --> His 39). Soluble TR stimulated erbB-4 tyrosine phosphorylation in MKN 28 gastric can cer cells, although it was weak compared to neuregulin-induced erbB-4 tyros ine phosphorylation; this suggests that TR might be a ligand for erbB-4- or erbB-4-related receptor tyrosine kinase, TR may have important roles in no rmal development of middle to late stages of embryos and maintenance of adu lt central nervous system tissues as high expression of TR mRNAs was observ ed in these tissues. The modular features suggest multiple roles for TR; th ese include functioning as a ligand for erbB-receptor, a regulator of TGF-b eta-related growth factor signaling by direct interaction through the folli statin modules, and a G-protein-coupled receptor. (C) 1999 Academic Press.