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

含有卵泡抑素模块的新型 EGF 样分子在胃肠粘膜中的作用

• 批准号: 09470139
• 负责人: SAKAMOTO Choitsu
• 金额: $ 8.51万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470139/
• 关键词: EGF; follistatin; stomach fibroblast; tomoregulin (TR); erbB4; gastric epithelial cells; fomoregulin(TR)

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.

我们从胃成纤维细胞中分离到一个编码新蛋白的基因，该蛋白含有两个可能结合TGF β相关生长因子的卵泡抑素模块和一个与EGF/Neuregulin（NRG）家族生长因子密切相关的表皮生长因子（EGF）样结构域。序列分析揭示了新的cDNA克隆，其蛋白质产物被指定为tomoregulin（TR），并由至少三种亚型，其区别于它们的胞质结构域。TR的前体蛋白（Pro-TR）是糖基化的跨膜蛋白。两种分泌的可溶性形式导致蛋白水解裂解区分的存在或不存在或不存在的EGF样结构域。与EGF/NRG家族生长因子相比，TR的EGF样结构域是高度保守的，除了在位置39处的精氨酸被组氨酸取代（Arg-> His 39）。在MKN 28胃癌细胞中，可溶性TR刺激erbB-4酪氨酸磷酸化，但其作用弱于neuregulin诱导的erbB-4酪氨酸磷酸化，提示TR可能是erbB-4或erbB-4相关受体酪氨酸激酶的配体。这些包括作为erbB受体的配体、通过卵泡抑素模块直接相互作用的TGFβ相关生长因子信号传导的调节剂和G蛋白偶联受体。

项目成果

Wada K: "gastric cpilhelial cells secrele a PPGF-like peptide,apotent mitogen for human gastric fibroblasts" Proc Sor Exp Biol Med. 217. 109-115 (1998)

Wada K：“胃毛细血管细胞分泌 PPGF 样肽，是人胃成纤维细胞的弱有丝分裂原”Proc Sor Exp Biol Med。

Uchida T, Wada K, Akamatsu T, Yonezawa M, et al: "A novel epidermal growth falter like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB4"Biochem Biophys Res Commun. 266. 593-602 (1999)

Uchida T、Wada K、Akamatsu T、Yonezawa M 等人：“一种包含两个卵泡抑素模块的新型表皮生长衰退样分子可刺激 erbB4 的酪氨酸磷酸化”Biochem Biophys Res Commun。

Uchida T,Wada K,Akamatsu T,Yonezawa M, et al: "A novel epidermal growth factor-like molecule containing two follistatin mo***les stimulates tyrosine phosphorylation of erbB4"Biochem Biophys Res Commun. 266. 593-602 (1999)

Uchida T、Wada K、Akamatsu T、Yonezawa M 等人：“一种含有两个卵泡抑素分子的新型表皮生长因子样分子可刺激 erbB4 的酪氨酸磷酸化”Biochem Biophys Res Commun。

Wada K, Sakamoto C, Matsuda K, Uchida T, Noguchi H, et al: "Gastric epithelial cells secrete a PDGF-like peptide, a potent mitogen for human gastric fibroid"Proc.Soc.Exp,Biol.Med.. 217. 109-115 (1998)

Wada K、Sakamoto C、Matsuda K、Uchida T、Noguchi H 等人：“胃上皮细胞分泌 PDGF 样肽，这是人胃纤维瘤的有效有丝分裂原”Proc.Soc.Exp，Biol.Med.. 217。

Noguchi H,Sakamoto C,Wada K,Akamatsu T,Uchida T, et al: "Expression of heregulinα, erbB2 and erbB3 and their influences on proliferation of gastric epifhelial cells"Gastroenterology. 117. 1119-1127 (1999)

Noguchi H、Sakamoto C、Wada K、Akamatsu T、Uchida T 等：“heregulinα、erbB2 和 erbB3 的表达及其对胃上皮细胞增殖的影响”胃肠病学。