The stress- and inflammatory cytokine-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor is mediated by p38 MAPK, distinct from the 12-O-tetradecanoylphorbol-13-acetate- and lysophosphatidic acid-induced signaling cascades
The stress- and inflammatory cytokine-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor is mediated by p38 MAPK, distinct from the 12-O-tetradecanoylphorbol-13-acetate- and lysophosphatidic acid-induced signaling cascades
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DOI：
10.1074/jbc.m211835200
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发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Mekada, E
中科院分区：
文献类型：
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作者：
Takenobu, H;Yamazaki, A;Mekada, E
肝素结合表皮生长因子样生长因子（HB-EGF）是一种重要的生长因子，参与多种生理和病理过程。HB-EGF以膜锚定形式（pro-HBEGF）合成，pro-HB-EGF在细胞表面通过称为“胞外域脱落”的机制裂解，产生可溶性HB-EGF。“我们在这里表明，Vero细胞中pro-HB-EGF的胞外域脱落是由各种应激诱导刺激诱导的，包括紫外线、渗透压、过氧化和翻译抑制剂。促炎细胞因子白细胞介素-1 β也刺激了pro-HB-EGF的胞外域脱落。p38 MAPK的抑制剂（SB 203580）或p38 MAPK的显性负性（dn）形式的表达抑制了pro-HB-EGF的应激诱导的胞外域脱落，而JNK的抑制剂（SP 600125）或dnJNK 1的表达则没有。12-O-十四酰基佛波醇-13-乙酸酯（TPA）和溶血磷脂酸（LPA）也是Vero细胞中pro-HB-EGF脱落的有效诱导剂。应激诱导的pro-HB-EGF脱落不受TPA或LPA诱导的pro-HB-EGF脱落抑制剂或TPA或LPA诱导的pro-HB-EGF脱落途径中涉及的dn形式分子的抑制。相反，SB 203580或dnp 38 MAPK不抑制TPA或LPA诱导的pro-HB-EGF脱落。这些结果表明，应激诱导的pro-HB-EGF脱落是由p38 MAPK介导的，并且应激诱导的信号传导途径不同于TPA或LPA诱导的pro-HB-EGF脱落途径。
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a critical growth factor for a number of physiological and pathological processes. HB-EGF is synthesized as a membrane-anchored form (pro-HBEGF), and pro-HB-EGF is cleaved at the cell surface to yield soluble HB-EGF by a mechanism called "ectodomain shedding." We show here that the ectodomain shedding of pro-HB-EGF in Vero cells is induced by various stress-inducing stimuli, including UV light, osmotic pressure, hyperoxidation, and translation inhibitors. The pro-inflammatory cytokine interleukin-1beta also stimulated the ectodomain shedding of pro-HB-EGF. An inhibitor of p38 MAPK (SB203580) or the expression of a dominant-negative (dn) form of p38 MAPK inhibited the stress-induced ectodomain shedding of pro-HB-EGF, whereas an inhibitor of JNK (SP600125) or the expression of dnJNK1 did not. 12-O-Tetradecanoylphorbol-13-acetate (TPA) and lysophosphatidic acid (LPA) are also potent inducers of pro-HB-EGF shedding in Vero cells. Stress-induced pro-HB-EGF shedding was not inhibited by the inhibitors of TPA- or LPA-induced pro-HB-EGF shedding or by dn forms of molecules involved in the TPA- or LPA-induced pro-HB-EGF shedding pathway. Reciprocally, SB203580 or dnp38 MAPK did not inhibit TPA- or LPA-induced pro-HB-EGF shedding. These results indicate that stress-induced pro-HB-EGF shedding is mediated by p38 MAPK and that the signaling pathway induced by stress is distinct from the TPA- or LPA-induced pro-HB-EGF shedding pathway.