Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways
Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways
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DOI：
10.1074/jbc.m111.229252
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发表时间：
2011-05-27
影响因子：
4.8
通讯作者：
Cohn, Steven M.
中科院分区：
文献类型：
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作者：
Brodrick, Brooks;Vidrich, Alda;Cohn, Steven M.
成纤维细胞生长因子受体-3(FGFR-3)在发育中的肠道中的表达仅限于隐窝下部的未分化上皮细胞。我们之前的研究表明，缺乏功能性FGFR-3的小鼠小肠中的Paneth细胞数量显著减少。在这里，我们使用Caco 2细胞来研究FGFR-3信号是否可以通过其对TCF4/β-catenin的影响或通过该受体下游的其他信号途径直接调节Paneth细胞分化标志物的表达。经FGFR-3配体或表达FGFR-3(K650E)的Caco 2细胞处理后，人α-防御素5和6(HD5和HD6)和Paneth细胞溶菌酶等成熟Paneth细胞特有的基因表达显著增加，而肠道细胞分化标志物减少。FGFR-3信号的激活维持了高水平的β-catenin mRNA表达，导致TCF4/β-catenin调节的CCo2细胞转录活性增加。TCF4/β-连环蛋白通路的持续活性是诱导Paneth细胞标志物所必需的。除了FGFR-3对TCF4/β-catenin活性的影响外，FGFR-3激活MAPK通路也是诱导Paneth细胞标志物所必需的。这些研究表明，FGFR-3下游多个独立信号通路的协同激活参与了Paneth细胞分化的调节。
Fibroblast growth factor receptor-3 (FGFR-3) expression in the developing intestine is restricted to the undifferentiated epithelial cells within the lower portion of the crypt. We previously showed that mice lacking functional FGFR-3 have a significant decrease in the number of Paneth cells in the small intestine. Here, we used Caco2 cells to investigate whether FGFR-3 signaling can directly modulate expression of Paneth cell differentiation markers through its effects on TCF4/beta-catenin or through other signaling pathways downstream of this receptor. Caco2 cells treated with FGFR-3 ligands or expressing FGFR-3(K650E), a constitutively active mutant, resulted in a significantly increased expression of genes characteristic of mature Paneth cells, including human alpha-defensins 5 and 6 (HD5 and HD6) and Paneth cell lysozyme, whereas enterocytic differentiation markers were reduced. Activation of FGFR-3 signaling sustained high levels of beta-catenin mRNA expression, leading to increased TCF4/beta-catenin-regulated transcriptional activity in Caco2 cells. Sustained activity of the TCF4/beta-catenin pathway was required for the induction of Paneth cell markers. Activation of the MAPK pathway by FGFR-3 is also required for the induction of Paneth cell markers in addition to and independent of the effect of FGFR-3 on TCF4/beta-catenin activity. These studies suggest that coordinate activation of multiple independent signaling pathways downstream of FGFR-3 is involved in regulation of Paneth cell differentiation.