Role of a novel EGF-like molecule containing follistatin modules in the gastrointestinal mucosa

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We have isolated a gene from stomach fibroblasts encoding novel proteins containing two follistatin modules which might bind TGF β-related growth factors and a single epidermal growth factor (EGF)-like domain which is closely related to EGF/Neuregulin (NRG) family growth factors. Sequence analysis revealed novel cDNA clones, the protein products of which were designated tomoregulin (TR) and consisted of at least three isoforms which were distinguished by their cytoplasmic domains. The cytoplasmic domains in all isolorms were short and contained potential G-protein activating motifs.Precursors of TR (Pro-TR) are gloycosylated transmembrance proteins. Two secreted soluble forms resulted from proteolytic cleavage were distinguished by the presence or absence or absence of the EGF-like domain. The EGF-like domain of TR was highly conserved compared to EGF/NRG family growth factors was 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 cancer cells, although it was weak compared to neuregulin-induced erbB-4 tyrosine phosphrylation ; this suggests that TR might be a ligand for erbB-4 or erbB-4 related receptor tyrosine kinase.The modular features suggest multiple roles for TR ; these include functioning as a ligand for erbB- receptor, a regulator of TGFβ-related growth factor signaling by direct interaction through the follistatin modules, and a G-protein coupled receptor.