Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.
Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.
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DOI：
10.1083/jcb.128.3.433
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发表时间：
1995-02
影响因子：
7.8
通讯作者：
Massague, J
中科院分区：
文献类型：
--
作者：
Arribas, J;Massague, J
膜蛋白胞外域的裂解和释放是一个影响许多细胞表面蛋白的受调节过程，在很大程度上仍然没有表征。为了研究细胞表面蛋白是否通过共享机制或通过多个独立机制被切割，我们诱变中国仓鼠卵巢（CHO）细胞，并选择不能切割膜锚定转化生长因子α（TGF-α）的克隆。这些克隆中TGF-α裂解的缺陷在用蛋白激酶C（PKC）激活剂PMA处理细胞时最明显，PMA刺激野生型细胞中的TGF-α裂解。突变体克隆在TFG-alpha表达、转运至细胞表面或周转方面没有缺陷。伴随着TGF-α切割的丧失，这些克隆丧失了响应PMA切割许多结构上不相关的膜蛋白的能力。这些蛋白质包括β-淀粉样前体蛋白（β-APP），其裂解为分泌形式避免转化为淀粉样肽A β，以及一组细胞表面蛋白，其释放到培养基中在野生型CHO细胞中受到PMA刺激，但在突变体中不受刺激。突变阻止PKC依赖性以及PKC非依赖性机制的切割，从而影响在这些不同信号传导机制下游起作用的重要组分。我们建议，调节切割和分泌的膜蛋白胞外域介导的一个共同的系统，其组件响应多种激活剂和作用于不同的结构和功能的易感蛋白。
Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC- dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.