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Functional analysis of a novel follistatin-like molecule in gastrointestinal lesion.

新型卵泡抑素样分子在胃肠道病变中的功能分析。

基本信息

批准号：
11670543
负责人：
WADA Ken
金额：
$ 2.24万
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 (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670543/
关键词：
follistatin epidermal growth factor gastric fibroblast 胃線維芽細胞

项目摘要

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 isoforms were short, as predicted from the sequences, and contained potential G-protein activating motifs. Precursors of TR (Pro-TR) are glycosylated transmembrane proteins. Two secreted soluble forms resulted from proteolytic cleavage were distinguished by the presence or absence of the EGF-like domain. The EGF-like domain of TR was highly conserved compared to EGF/NRG family growth factors with the exception of an arginine to histidine substitution at position 39 (Arg->His 39). Arg39 has been shown to be essential for receptor recognition in EGF.Consistent with this hypothesis, the purified soluble TR extracellular domain failed to activate the EGF receptor, erbB-2 and erbB-3 in certain cell lines, indicating TR was not a ligand for them. However, in MKN 28 gastric cancer cells, soluble TR stimulated erbB-4 tyrosine phosphorylation, although it was weak compared to neuregulin-induced erbB-4 tyrosine 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 normal development of middle to late stages of embryos and maintenance of adult central nervous system tissues as high expression of TR mRNAs was observed in these tissues. The modular features suggest multiple roles for TR ; these include functioning as a ligand for erbB-receptor, a regulator of TGF β-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。正如序列预测的那样，所有亚型的胞质结构域都很短，并且包含潜在的G蛋白激活基序。TR的前体（Pro-TR）是糖基化的跨膜蛋白。两个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的EGF样结构域。TR的EGF样结构域与EGF/NRG家族生长因子相比是高度保守的，除了第39位的精氨酸被组氨酸取代（Arg->His 39）。Arg 39在EGF受体识别中起重要作用，与此假设一致，在某些细胞系中，纯化的可溶性TR胞外结构域不能激活EGF受体erbB-2和erbB-3，表明TR不是它们的配体。然而，在MKN 28胃癌细胞中，可溶性TR刺激erbB-4酪氨酸磷酸化，虽然它是弱的神经调节蛋白诱导的erbB-4酪氨酸磷酸化相比，这表明TR可能是erbB-4或erbB-4相关受体酪氨酸激酶的配体。TR基因在中晚期胚胎的正常发育和成年中枢神经系统组织的维持中可能起重要作用，因为在这些组织中观察到TR mRNA的高表达。模块化特征表明TR具有多种作用;这些作用包括作为erbB受体的配体、通过卵泡抑素模块直接相互作用的TGF β相关生长因子信号传导的调节剂以及G蛋白偶联受体。