Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane
Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane
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DOI：
10.1152/ajpgi.00297.2010
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发表时间：
2010-11-01
影响因子：
4.5
通讯作者：
Lynch, John P.
中科院分区：
文献类型：
--
作者：
Funakoshi, Shinsuke;Kong, Jianping;Lynch, John P.
Funakoshi S，Kong J，克里塞MA，Dang L，Dang D，Lynch JP.肠特异性转录因子Cdx 2通过增强E-钙粘蛋白向细胞膜的运输来诱导E-钙粘蛋白功能。美国生理学杂志胃肠和肝脏生理学299：G1054-G1067，2010。首次发表于2010年7月29日; doi：10.1152/ajpgi.00297.2010.- Cdx 2是正常肠上皮细胞发育所需的一种丝氨酸特异性转录因子。Cdx 2调控细胞特异性基因的表达，并诱导细胞粘附和柱状形态发生。Cdx 2还具有肿瘤抑制特性，包括减少结肠癌细胞增殖和细胞侵袭，后者是由于其对细胞粘附的影响。E-钙粘蛋白是粘附连接形成和肠细胞极性建立所需的细胞粘附蛋白。本研究的目的是阐明Cdx 2调节E-cadherin功能的机制。两个结肠癌细胞系中，Cdx 2的表达与细胞间粘附增加和细胞迁移减少。在这两种细胞系中，Cdx 2并没有直接改变E-钙粘蛋白水平，但增加其贩运到细胞膜室。Cdx 2通过改变受体酪氨酸激酶（RTK）活性增强了这种运输。Cdx 2表达降低了磷酸化Abl和磷酸化Rac水平，这是RTK的下游效应物。特异性化学抑制或c-Abl激酶的短干扰RNA（shRNA）敲低表型模拟Cdx 2的细胞-细胞粘附作用。在科洛205细胞中，Cdx 2减少PDGF受体和IGF-I受体活化。这是介导的小窝蛋白-1，这是由Cdx 2诱导。靶向小凹蛋白-1的shRNA敲低恢复了PDGF受体并逆转了E-钙粘蛋白膜运输，尽管Cdx 2表达。我们的结论是Cdx 2调节E-钙粘蛋白的功能，间接干扰RTK活性和增强E-钙粘蛋白贩运到细胞膜隔室。这种新的机制推进Cdx 2的促分化和抗肿瘤特性，并表明Cdx 2可以通过调节蛋白质的膜运输广泛调节正常肠上皮细胞中的RTK活性。
Funakoshi S, Kong J, Crissey MA, Dang L, Dang D, Lynch JP. Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane. Am J Physiol Gastrointest Liver Physiol 299: G1054-G1067, 2010. First published July 29, 2010; doi: 10.1152/ajpgi.00297.2010.-Cdx2 is an intestine-specific transcription factor required for normal intestinal epithelium development. Cdx2 regulates the expression of intestine-specific genes and induces cell adhesion and columnar morphogenesis. Cdx2 also has tumor-suppressor properties, including the reduction of colon cancer cell proliferation and cell invasion, the latter due to its effects on cell adhesion. E-cadherin is a cell adhesion protein required for adherens junction formation and the establishment of intestinal cell polarity. The objective of this study was to elucidate the mechanism by which Cdx2 regulates E-cadherin function. Two colon cancer cell lines were identified in which Cdx2 expression was associated with increased cell-cell adhesion and diminished cell migration. In both cell lines, Cdx2 did not directly alter E-cadherin levels but increased its trafficking to the cell membrane compartment. Cdx2 enhanced this trafficking by altering receptor tyrosine kinase (RTK) activity. Cdx2 expression diminished phosphorylated Abl and phosphorylated Rac levels, which are downstream effectors of RTKs. Specific chemical inhibition or short interfering RNA (shRNA) knockdown of c-Abl kinase phenocopied Cdx2's cell-cell adhesion effects. In Colo 205 cells, Cdx2 reduced PDGF receptor and IGF-I receptor activation. This was mediated by caveolin-1, which was induced by Cdx2. Targeted shRNA knockdown of caveolin-1 restored PDGF receptor and reversed E-cadherin membrane trafficking, despite Cdx2 expression. We conclude that Cdx2 regulates E-cadherin function indirectly by disrupting RTK activity and enhancing E-cadherin trafficking to the cell membrane compartment. This novel mechanism advances Cdx2's prodifferentiation and antitumor properties and suggests that Cdx2 may broadly regulate RTK activity in normal intestinal epithelium by modulating membrane trafficking of proteins.