Involvement of IQGAP3, a Regulator of Ras/ERK-Related Cascade, in Hepatocyte Proliferation in Mouse Liver Regeneration and Development
Involvement of IQGAP3, a Regulator of Ras/ERK-Related Cascade, in Hepatocyte Proliferation in Mouse Liver Regeneration and Development
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DOI：
10.1002/jcp.21798
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发表时间：
2009-09-01
影响因子：
5.6
通讯作者：
Tsukita, Sachiko
中科院分区：
文献类型：
--
作者：
Kunimoto, Koshi;Nojima, Hisashi;Tsukita, Sachiko
肝细胞增殖的时空调控是肝再生的关键问题。在这里，我们研究了IQGAP3在正常肝、再生肝以及发育中肝中的表达和定位，IQGAP3最近被报道为一种Ras/RAC/CDC42结合的增殖因子，与上皮型细胞中的细胞-细胞接触有关。同时，检测RAC/Cdc42结合IQGAP 1/2的表达和定位。IQGAP3在增殖标记物Ki-67阳性的增殖期肝细胞中有特异性表达，在肝再生和发育过程中肝细胞的mRNAs和蛋白表达水平显著升高。在免疫荧光中，IQGAP3在肝细胞的细胞-细胞接触处高度浓缩。IQGAP I和IQGAP2分别在正常肝、再生肝和发育中的Kupffer和肝窦内皮细胞中特异表达。在CCl4诱导的(但不是部分肝切除诱导的)肝再生中，IQGAP I的表达增加，而IQGAP2的表达没有增加。IQGAP3在肝细胞中的独占表达/定位可能反映了IQGAP3/RAS/ERK信号级联除了先前已发现的信号通路外，还可能通过整合细胞与细胞接触相关的增殖信号事件而参与肝细胞增殖。另一方面，IQGAP1/2/3的RAC/CDC42结合特性可能与不同的重塑模式有关，因为不同的策略诱导了肝细胞的增殖、肝部分切除、CCL4损伤或胚胎发育。因此，RAS和RAS同源(RHO)家族蛋白RAC/CDC42的功能协调可能在肝脏的再生和发育中发挥关键作用。J.细胞。物理。220：621-631,2009。(C)2009年Wiley-Liss，Inc.
The spatio-temporal regulation of hepatocyte proliferation is a critical issue in liver regeneration. Here, in normal and regenerating liver as well as in developing liver, we examined its expression/localization of IQGAP3, which was most recently reported as a Ras/Rac/Cdc42-binding proliferation factor associated with cell-cell contacts in epithelial-type cells. In parallel, the expression/localization of Rac/Cdc42-binding IQGAP 1/2 was examined. IQGAP3 showed a specific expression in proliferating hepatocytes positive for the proliferating marker Ki-67, the levels of expressions of mRNAs and proteins were significantly increased in hepatocytes in liver regeneration and development. In immunofluorescence, IQGAP3 was highly enriched at cell-cell contacts of hepatocytes. IQGAP I and IQGAP2 were exclusively expressed in Kupffer and sinusoidal endothelial cells, respectively, in normal, regenerating, and developing liver. The expression of IQGAP I, but not of IQGAP2, was increased in CCl4-induced (but not in partial hepatectomy-induced) liver regeneration. Exclusive expression/localization of IQGAP3 to hepatocytes in the liver likely reflects the specific involvement of the IQGAP3/Ras/ERK signaling cascade in hepatocyte proliferation in addition to the previously identified signaling pathways, possibly by integrating cell-cell contact-related proliferating signaling events. On the other hand, the Rac/Cdc42-binding properties of IQGAP1/2/3 may be related to the distinct modes of remodeling due to the different strategies which induced proliferation of liver cells; partial hepatectomy, CCl4 injury, or embryonic development. Thus, the functional orchestration of Ras and the Ras homologous (Rho) family proteins Rac/Cdc42 likely plays a critical role in liver regeneration and development. J. Cell. Physiol. 220: 621-631, 2009. (C) 2009 Wiley-Liss, Inc.