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Conversion of membrane-anchored HB-EGF into the soluble form.

将膜锚定的 HB-EGF 转化为可溶形式。

基本信息

批准号：
11694330
负责人：
MEKADA Eisuke
金额：
$ 3.9万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
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

项目摘要

The proteolytic piocessing of the extracellular domain, also referred to as ectodomain shedding, is observed in a number of membrane proteins Ectodomain shedding of membrane proteins affects the biological activities of membrane proteins Heparin-binding EGF-like growth factor(HB-EGF)is a member of the epidermal growth factor(EGF)family, and binds to and stimulates the phosphorylation of the EGF receptor. HB-EGF is synthesized as a membrane-anchored precursor protein(pioHB-EGF), but proHB-EGF is cleaved on the cell surface to yield a soluble growth factor. Although secreted mature HB-EGF(sHB-EGF)is a potent mitogen for a number of cell types, proHB-EGF may act as a negative regulator of cell proliferation. Thus, the processing of the juxtamembrane domain of proHB-EGF to sHB-EGF means the conversion of the mode of action of this growth factor from juxtacrine to paracrine, or the switching to an opposite activity for cell growth. Ectodomain shedding of proHB-EGF is induced by a number of stimuli including TPA and calcium ionophore, indicating that this cleavage is a regulated process. However, it is known that a significant amount of the ectodomain is constitutively shed even when cells are cultured in a normal culture medium without any particular stimuli. We revealed that constitutive cleavage as observed in a medium is a kind of stimuli-induced cleavage, mainly due to lysophosphatidic acid(LPA)in the serum. Studies on the signaling cascade downstream of LPA indicated that Ras-Raf-MEK cascade is critical for LPA-induced shedding. Results also indicated that the LPA-induced shedding pathway is distinct from the TPA-induced shedding pathway

在许多膜蛋白中观察到胞外结构域的蛋白水解作用，也称为胞外结构域脱落。膜蛋白的胞外结构域脱落影响膜蛋白的生物活性肝素结合EGF样生长因子（HB-EGF）是表皮生长因子（EGF）家族的成员，并且结合并刺激EGF受体的磷酸化。HB-EGF作为膜锚定前体蛋白（pioHB-EGF）合成，但proHB-EGF在细胞表面被切割以产生可溶性生长因子。虽然分泌的成熟HB-EGF（sHB-EGF）是一种有效的有丝分裂原的一些细胞类型，proHB-EGF可以作为一个负调节细胞增殖。因此，proHB-EGF的近膜结构域加工为sHB-EGF意味着该生长因子的作用模式从近分泌转变为旁分泌，或者转变为细胞生长的相反活性。proHB-EGF的胞外结构域脱落是由包括TPA和钙离子载体在内的许多刺激物诱导的，表明这种切割是一个受调节的过程。然而，已知即使当细胞在没有任何特定刺激的正常培养基中培养时，也有显著量的胞外域组成性脱落。我们发现，在培养基中观察到的组成性裂解是一种刺激诱导的裂解，主要是由于溶血磷脂酸（LPA）在血清中。对LPA下游信号级联的研究表明，Ras-Raf-MEK级联对于LPA诱导的脱落至关重要。结果还表明LPA诱导的脱落途径与TPA诱导的脱落途径不同