Galownia Niki C, Kushiro Keiichiro, Gong Yuan, Asthagiri Anand R
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
J Biol Chem. 2007 Jul 27;282(30):21758-66. doi: 10.1074/jbc.M703577200. Epub 2007 May 31.
Cell adhesion to the extracellular matrix is required to execute growth factor (GF)-mediated cell behaviors, such as proliferation. A major underlying mechanism is that cell adhesion enhances GF-mediated intracellular signals, such as extracellular signal-regulated kinase (Erk). However, because GFs use distinct mechanisms to activate Ras-Erk signaling, it is unclear whether adhesion-mediated enhancement of Erk signaling is universal to all GFs. We examined this issue by quantifying the dynamics of Erk signaling induced by epidermal growth factor, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) in NIH-3T3 fibroblasts. Adhesion to fibronectin-coated surfaces enhances Erk signaling elicited by epidermal growth factor but not by bFGF or PDGF. Unexpectedly, adhesion is not always a positive influence on GF-mediated signaling. At critical subsaturating doses of PDGF or bFGF, cell adhesion ablates Erk signaling; that is, adhesion desensitizes the cell to GF stimulation, rendering the signaling pathway unresponsive to GF. Interestingly, the timing of growth factor stimulation proved critical to the desensitization process. Erk activation significantly improved only when pre-exposure to adhesion was completely eliminated; thus, concurrent stimulation by GF and adhesion was able to partially rescue adhesion-mediated desensitization of PDGF- and bFGF-mediated Erk and Akt signaling. These findings suggest that adhesion-mediated desensitization occurs with rapid kinetics and targets a regulatory point upstream of Ras and proximal to GF receptor activation. Thus, adhesion-dependent Erk signaling is not universal to all GFs but, rather, is GF-specific with quantitative features that depend strongly on the dose and timing of GF exposure.
细胞与细胞外基质的粘附是执行生长因子（GF）介导的细胞行为（如增殖）所必需的。一个主要的潜在机制是细胞粘附增强了GF介导的细胞内信号，如细胞外信号调节激酶（Erk）。然而，由于GFs使用不同的机制来激活Ras-Erk信号，目前尚不清楚粘附介导的Erk信号增强是否对所有GFs都具有普遍性。我们通过量化表皮生长因子、碱性成纤维细胞生长因子（bFGF）和血小板衍生生长因子（PDGF）在NIH-3T3成纤维细胞中诱导的Erk信号动力学来研究这个问题。粘附于纤连蛋白包被的表面可增强表皮生长因子引发的Erk信号，但不能增强bFGF或PDGF引发的Erk信号。出乎意料的是，粘附并不总是对GF介导的信号产生积极影响。在PDGF或bFGF的临界亚饱和剂量下，细胞粘附会消除Erk信号；也就是说，粘附使细胞对GF刺激脱敏，使信号通路对GF无反应。有趣的是，生长因子刺激的时机对脱敏过程至关重要。只有当完全消除预先暴露于粘附时，Erk激活才会显著改善；因此，GF和粘附的同时刺激能够部分挽救PDGF和bFGF介导的Erk和Akt信号的粘附介导的脱敏。这些发现表明，粘附介导的脱敏以快速动力学发生，并靶向Ras上游且靠近GF受体激活的调节点。因此，粘附依赖性Erk信号并非对所有GFs都具有普遍性，而是具有GF特异性，其定量特征强烈依赖于GF暴露的剂量和时机。
