期刊
CELLULAR SIGNALLING
卷 21, 期 6, 页码 954-968出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.02.005
关键词
Nestin; Proliferation; Thrombin; EGFR transactivation; Vascular smooth muscle cells
类别
资金
- National Science Council, Executive Yuan, Taiwan [NSC96-2752-B-006-003-PAE, NSC96-2752-B-006-004-PAE, NSC96-2752-B-006-005-PAE]
Regulation of nestin gene expression is largely unknown despite that it is widely used as a progenitor cell marker. In this study, we showed that nestin expression is regulated by the thrombin-mediated EGFR transactivation in serum-deprived primary cultures of rat vascular smooth muscle cells (VSMCs). This resulted from the direct binding of thrombin to PAR-1 rather than indirectly affecting through the binding to thrombomodulin, as demonstrated by thrombomodulin RNAi. In this process, the PAR-1-induced c-Src plays a critical role through two routes; one was the direct intracellular phosphorylation of EGFR and the other was the extracellular activation of the MMP-2-mediated shedding of HB-EGF. The transactivated EGFR then led to the downstream Ras-Raf-ERK signaling axis, but not the p38 or JNK pathways. In addition, the EMSA experiment showed that the transcriptional factor Sp1 is critical for the thrombin-induced nestin expression in rat VSMCs. Furthermore, RNAi of nestin attenuated the thrombin-induced cell proliferation, indicating that thrombin-induced nestin expression and cell proliferation share the same EGFR transactivation mechanism. This study also suggested that nestin may play an important role in cell proliferation induced by the thrombin-mediated EGFR transactivation. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.
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