SHP-2是在大多数胚胎和成体组织中表达的酪氨酸磷酸酶。SHP-2调节许多细胞功能,包括生长,分化,迁移,和生存。遗传和生化证据表明,SHP-2是大多数酪氨酸激酶受体激活大鼠肉瘤病毒癌基因/细胞外信号调节激酶丝裂原激活蛋白激酶途径所必需的,以及G蛋白偶联和细胞因子受体。此外,SHP-2可以调节Janus激酶/信号转导和转录激活因子,核因子-κB,磷脂酰肌醇3-激酶/Akt,RhoA,河马,和Wnt/β-catenin信号通路。新的证据表明,SHP-2功能障碍是胃肠道疾病发病的关键因素,特别是在慢性炎症和癌症中。编码SHP-2的基因座内的变异与发展为溃疡性结肠炎和胃萎缩的易感性增加有关。此外,肠上皮细胞中SHP-2条件性缺失的小鼠迅速发展为严重结肠炎。同样,肝细胞特异性SHP-2缺失诱导肝脏炎症,导致衰老小鼠的再生增生和肿瘤的发展。然而,SHP-2基因最初被认为是一种原癌基因,因为在小儿白血病以及某些形式的肝癌和结肠癌中发现了该基因的激活突变.此外,SHP-2表达在胃癌和肝细胞癌中上调。值得注意的是,SHP-2在细胞毒素相关抗原A(CagA)的下游起作用,幽门螺杆菌的主要毒力因子,并且与胃癌的风险增加有关。进一步加剧了这种复杂性,最近的发现表明SHP-2也协调碳水化合物,脂质,和胆汁酸在肝脏和胰腺的合成。这篇综述旨在总结有关SHP-2在胃肠道中的生物学功能的最新知识和最新数据。
SHP-2 is a tyrosine phosphatase expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, migration, and survival. Genetic and biochemical evidence show that SHP-2 is required for rat sarcoma viral oncogene/extracellular signal-regulated kinases mitogen-activated protein kinase pathway activation by most tyrosine kinase receptors, as well as by G-protein-coupled and cytokine receptors. In addition, SHP-2 can regulate the Janus kinase/signal transducers and activators of transcription, nuclear factor-κB, phosphatidyl-inositol 3-kinase/Akt, RhoA, Hippo, and Wnt/β-catenin signaling pathways. Emerging evidence has shown that SHP-2 dysfunction represents a key factor in the pathogenesis of gastrointestinal diseases, in particular in chronic inflammation and cancer. Variations within the gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis and gastric atrophy. Furthermore, mice with conditional deletion of SHP-2 in intestinal epithelial cells rapidly develop severe colitis. Similarly, hepatocyte-specific deletion of SHP-2 induces hepatic inflammation, resulting in regenerative hyperplasia and development of tumors in aged mice. However, the SHP-2 gene initially was suggested to be a proto-oncogene because activating mutations of this gene were found in pediatric leukemias and certain forms of liver and colon cancers. Moreover, SHP-2 expression is up-regulated in gastric and hepatocellular cancers. Notably, SHP-2 functions downstream of cytotoxin-associated antigen A (CagA), the major virulence factor of Helicobacter pylori, and is associated with increased risks of gastric cancer. Further compounding this complexity, most recent findings suggest that SHP-2 also coordinates carbohydrate, lipid, and bile acid synthesis in the liver and pancreas. This review aims to summarize current knowledge and recent data regarding the biological functions of SHP-2 in the gastrointestinal tract.