Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling
Cell surface restriction of EGFR by a tenascin cytotactin-encoded EGF-like repeat is preferential for motility-related signaling
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DOI：
10.1002/jcp.21232
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发表时间：
2008-02-01
影响因子：
5.6
通讯作者：
Wells, Alan
中科院分区：
文献类型：
--
作者：
Iyer, Anand Krishnan V.;Tran, Kien T.;Wells, Alan
人terascin cytokine的第14个EGFL重复序列（Ten 14）以微摩尔亲和力激活表皮生长因子受体（EGFR）：然而，与EGF不同，Ten 14介导的EGFR激活不会导致受体内化。由于EGFR下游的不同信号传导途径已被证明是从质膜和胞质区域触发的，我们研究了与EGF相比，Ten 14介导的EGFR表面限制是否导致生物化学和细胞反应的改变。与迁移级联相关的分子被激活到一个相对更大的程度上响应Ten 14，与增殖相关的级联非常弱的激活。磷脂酶C γ（PLC γ）和m-钙蛋白酶的激活，分别与片足突出和尾部收缩，甚至在亚饱和剂量的Ten 14。然而，ERK/MAPK，p90 RSK和Elk 1的激活，影响增殖的因素，即使在高Ten 14浓度下仍然很低。在4 ℃下，EGF处理的细胞观察到类似的激活曲线，这是一种限制受体内化的策略。我们证明了这种改变的信号传导对生物物理反应的并发效应-在激活PLC γ的10 - 14水平下观察到持续的迁移，但没有显著刺激增殖。在这里，我们提出了一类新的EGFR配体，可以潜在的信号作为细胞外基质的一部分，触发特定的细胞内信号级联反应，导致从其他多效性受体的定向细胞反应。这项工作扩展了EGFL重复序列作为细胞外基质的一部分以受限方式呈现的信号传导范例。
The 14th EGFL-repeat (Ten 14) of human terascin cytotactin activates the epidermal growth factor receptor (EGFR) with micromolar affinity: however, unlike EGF, Ten14-mediated activation of EGFR does not lead to receptor internalization. As the divergent signaling pathways downstream of EGFR have been shown to be triggered from plasma membrane and cytosolic locales, we investigated whether Ten14-mediated surface restriction of EGFR resulted in altered biochemical and cellular responses as compared to EGF. Molecules associated with migratory cascades were activated to a relatively greater extent in response to Ten14, with very weak activation of proliferation-associated cascades. Activation of phospholipase C gamma(PLC gamma) and m-calpain, associated with lamellipod protrusion and tail retraction, respectively, were noted at even at sub-saturating doses of Ten14. However, activation of ERK/MAPK, p90RSK, and Elk1, factors affecting proliferation, remained low even at high Ten14 concentrations. Similar activation profiles were observed for EGF-treated cells at 4 degrees C, a maneuver that limits receptor internalization. We demonstrate a concurrent effect of such altered signaling on biophysical responses-sustained migration was observed at levels of Ten 14 that activated PLC gamma, but did not stimulate proliferation significantly. Here, we present a novel class of EGFR ligands that can potentially signal as a part of the extracellular matrix, triggering specific intracellular signaling cascades leading to a directed cellular response from an otherwise pleiotropic receptor. This work extends the signaling paradigm of EGFL repeat being presented in a restricted fashion as part of the extracellular matrix.