Loss of protein tyrosine phosphatase N2 potentiates epidermal growth factor suppression of intestinal epithelial chloride secretion
Loss of protein tyrosine phosphatase N2 potentiates epidermal growth factor suppression of intestinal epithelial chloride secretion
复制标题
DOI：
10.1152/ajpgi.00106.2010
复制
发表时间：
2010-10-01
影响因子：
4.5
通讯作者：
McCole, Declan F.
中科院分区：
文献类型：
--
作者：
Scharl, Michael;Rudenko, Ivan;McCole, Declan F.
克罗恩病候选基因——非受体型蛋白酪氨酸磷酸酶2（PTPN2）已被证明可调节成纤维细胞中表皮生长因子（EGF）诱导的磷脂酰肌醇3 - 激酶（PI3K）的活化。在肠上皮细胞（IECs）中，EGF诱导的EGF受体（EGFR）活化以及PI3K的募集在调节许多细胞功能（包括依赖Ca²⁺的Cl⁻分泌）中起关键作用。此外，EGFR还作为其他非生长因子受体配体（如促炎细胞因子干扰素 - γ）的信号传导通道。在此，我们研究了PTPN2在调节IECs中EGFR信号传导以及类似于依赖Ca²⁺的Cl⁻分泌过程中的可能作用。在T - 84细胞中，PTPN2敲低增强了EGF诱导的EGFR酪氨酸磷酸化。特别是，PTPN2敲低促进了EGF诱导的EGFR残基Tyr - 992和Tyr - 1068的磷酸化，随后导致催化性PI3K亚基p110与EGFR的结合增加以及下游标志物Akt的磷酸化升高。作为一种功能性结果，PTPN2的缺失增强了EGF对氨甲酰胆碱刺激的依赖Ca²⁺的Cl⁻分泌的抑制作用。相反，PTPN2敲低既不影响干扰素 - γ诱导的EGFR反式激活，也不影响EGF或干扰素 - γ诱导的ERK1/2磷酸化。总之，我们的数据确定了PTPN2在IECs中响应EGF而非干扰素 - γ调节EGFR信号传导中的作用。PTPN2的敲低使EGFR信号转导趋向于增加PI3K活化以及增强对上皮氯化物分泌反应的抑制。此外，我们的研究结果表明，IECs中PTPN2功能失调会导致由EGFR调节的肠上皮功能的控制发生改变。
The Crohn's disease candidate gene, protein tyrosine phosphatase nonreceptor type 2 (PTPN2), has been shown to regulate epidermal growth factor (EGF)-induced phosphatidylinositol 3-kinase (PI3K) activation in fibroblasts. In intestinal epithelial cells (IECs), EGF-induced EGF receptor (EGFR) activation and recruitment of PI3K play a key role in regulating many cellular functions including Ca2+-dependent Cl- secretion. Moreover, EGFR also serves as a conduit for signaling by other non-growth factor receptor ligands such as the proinflammatory cytokine, IFN-gamma. Here we investigated a possible role for PTPN2 in the regulation of EGFR signaling and Ca2+-dependent Cl similar to secretion in IECs. PTPN2 knockdown enhanced EGF-induced EGFR tyrosine phosphorylation in T-84 cells. In particular, PTPN2 knockdown promoted EGF-induced phosphorylation of EGFR residues Tyr-992 and Tyr-1068 and led subsequently to increased association of the catalytic PI3K subunit, p110, with EGFR and elevated phosphorylation of the downstream marker, Akt. As a functional consequence, loss of PTPN2 potentiated EGF-induced inhibition of carbachol-stimulated Ca2+-dependent Cl- secretion. In contrast, PTPN2 knockdown affected neither IFN-gamma-induced EGFR transactivation nor EGF- or IFN-gamma-induced phosphorylation of ERK1/2. In summary, our data establish a role for PTPN2 in the regulation of EGFR signaling in IECs in response to EGF but not IFN-gamma. Knockdown of PTPN2 directs EGFR signaling toward increased PI3K activation and increased suppression of epithelial chloride secretory responses. Moreover, our findings suggest that PTPN2 dysfunction in IECs leads to altered control of intestinal epithelial functions regulated by EGFR.