Intestinal trefoil factor induces inactivation of extracellular signal-regulated protein kinase in intestinal epithelial cells
Intestinal trefoil factor induces inactivation of extracellular signal-regulated protein kinase in intestinal epithelial cells
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DOI：
10.1073/pnas.95.1.178
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发表时间：
1998-01-06
影响因子：
11.1
通讯作者：
Podolsky, DK
中科院分区：
文献类型：
--
作者：
Kanai, M;Mullen, C;Podolsky, DK
肠三叶因子（Intestinal trefoil factor，ITF）是一种小而致密的蛋白酶抗性肽，在大肠和小肠的杯状细胞中大量表达，虽然ITF的多种生物学活性已被鉴定，包括促进伤口愈合、刺激上皮细胞迁移和保护肠上皮屏障，但对ITF介导其生理功能的信号传导事件知之甚少。在IEC-6细胞（一种不表达内源性三叶肽的非转化的肠上皮细胞系）中检测了外源性ITF对促分裂原活化蛋白激酶（MAPK）信号级联的影响。用ITF刺激导致细胞外信号相关蛋白激酶（ERK）活性的快速降低和伴随的ERK酪氨酸磷酸化的降低。ITF还降低了由转化生长因子-α或佛波醇12-肉豆蔻酸酯13-乙酸酯诱导的ERK活性的激活，转化生长因子-α通过表皮生长因子受体将细胞外刺激与Ras/Raf/MEK/ERK通路联系起来，佛波醇12-肉豆蔻酸酯13-乙酸酯通过蛋白激酶C激活Raf。ITF诱导的ERK活性抑制被酪氨酸和双特异性磷酸酶抑制剂原钒酸钠阻断。总之，ITF通过激活酪氨酸或双特异性磷酸酶导致ERK和MAPK通路的抑制。
Intestinal trefoil factor (ITF), a small, compact protease-resistant peptide, is abundantly expressed in goblet cells of large and small intestine, Although several biological activities of ITF have been identified, including promotion of wound healing, stimulation of epithelial cell migration, and protection of intestinal epithelial barrier, little is known about signaling events through which ITF mediates its physiological function, In this study, the effects of exogenous ITF on mitogen-activated protein kinase (MAPK) signaling cascades were examined in IEC-6 cells, a nontransformed intestinal epithelial cell line that does not express endogenous trefoil peptides, Stimulation with ITF resulted in rapid decrease in extracellular signal-related protein kinase (ERK) activity and concomitant reduced ERK tyrosine phosphorylation. ITF also decreased activation of ERK activity induced by either transforming growth factor-alpha, which links extracellular stimuli to the Ras/Raf/MEK/ERK pathway via the epidermal growth factor receptor, or phorbol 12-myristate 13-acetate, which activates Raf through protein kinase C. ITF-induced inhibition of ERK activity was blocked by an inhibitor of tyrosine and dual-specific phosphatases, sodium orthovanadate, In summary, ITF leads to inhibition of ERK and the MAPK pathway through activation of tyrosine or dual-specific phosphatase.