ARHGEF11,即Rho鸟苷酸交换因子11,是一种编码Rho家族鸟苷酸交换因子(GEF)的基因。Rho GEFs是一类重要的信号传导蛋白,能够激活Rho家族小GTPases,如RhoA,从而调节细胞骨架重塑、细胞迁移、细胞粘附和细胞增殖等多种细胞过程。ARHGEF11基因位于人类1号染色体上,其表达和功能在多种生物学过程中发挥重要作用,包括胰岛素信号传导、肿瘤发生和发育等。
研究表明,ARHGEF11基因的变异与多种疾病的发生发展相关。例如,在Pima印第安人中,ARHGEF11基因的变异与胰岛素抵抗和2型糖尿病的发生风险增加相关[1]。此外,ARHGEF11基因的变异还与肝细胞癌的进展相关,ARHGEF11的表达上调可以促进肝细胞癌细胞的增殖和上皮-间质转化(EMT),并激活β-catenin信号通路[2]。
ARHGEF11基因的变异还与一些神经系统的疾病相关。例如,ARHGEF11::NTRK1融合基因阳性的脊髓弥漫性儿童型高级别胶质瘤患者,经过Entrectinib治疗后,可以诱导出持久性的反应[3]。此外,ARHGEF11基因的变异还与精神分裂症的发生风险相关[6]。
ARHGEF11基因的变异还与肾脏疾病相关。例如,在Dahl盐敏感性大鼠中,ARHGEF11基因的变异可以通过Rho-ROCK信号通路影响肾脏损伤[7][8]。此外,ARHGEF11基因的变异还与胎儿巨大症的发生相关。ARHGEF11基因的表达上调可以抑制胰岛素信号传导,从而影响胎儿的生长发育[4]。
ARHGEF11基因的变异还与上皮紧密连接的完整性相关。ARHGEF11基因的剪接变异可以通过RhoA激活和肌球蛋白轻链(MLC)磷酸化影响上皮紧密连接的完整性[5]。
综上所述,ARHGEF11基因的变异与多种疾病的发生发展相关,包括胰岛素抵抗、2型糖尿病、肝细胞癌、脊髓弥漫性儿童型高级别胶质瘤、精神分裂症、肾脏疾病和胎儿巨大症等。ARHGEF11基因的功能研究有助于深入理解Rho GEFs在细胞信号传导和疾病发生中的作用机制,为相关疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Ma, Lijun, Hanson, Robert L, Que, Lorem N, Shuldiner, Alan R, Baier, Leslie J. 2007. Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in Pima Indians. In Diabetes, 56, 1454-9. doi:. https://pubmed.ncbi.nlm.nih.gov/17287471/
2. Du, Jinpeng, Zhu, Zexin, Xu, Lin, Yuan, Kefei, Zeng, Yong. 2020. ARHGEF11 promotes proliferation and epithelial-mesenchymal transition of hepatocellular carcinoma through activation of β-catenin pathway. In Aging, 12, 20235-20253. doi:10.18632/aging.103772. https://pubmed.ncbi.nlm.nih.gov/33122451/
3. Miyachi, Mitsuru, Sugimoto, Yohei, Sugitatsu, Yuya, Konishi, Eiichi, Iehara, Tomoko. 2023. Entrectinib treatment induces a durable response against ARHGEF11::NTRK1 fusion gene-positive spinal cord diffuse pediatric-type high-grade glioma. In Pediatric blood & cancer, 70, e30513. doi:10.1002/pbc.30513. https://pubmed.ncbi.nlm.nih.gov/37393426/
4. Zhang, Wanyi, Su, Rina, Lin, Li, Yang, Huixia. 2017. ARHGEF11 affecting the placental insulin signaling pathway in fetal macrosomia of normal glucose tolerance pregnant women. In Placenta, 63, 7-14. doi:10.1016/j.placenta.2017.12.010. https://pubmed.ncbi.nlm.nih.gov/29486856/
5. Lee, SungKyoung, Cieply, Benjamin, Yang, Yueqin, Chan, Patricia, Carstens, Russ P. . Esrp1-Regulated Splicing of Arhgef11 Isoforms Is Required for Epithelial Tight Junction Integrity. In Cell reports, 25, 2417-2430.e5. doi:10.1016/j.celrep.2018.10.097. https://pubmed.ncbi.nlm.nih.gov/30485810/
6. Mizuki, Yutaka, Takaki, Manabu, Okahisa, Yuko, Ujike, Hiroshi, Uchitomi, Yosuke. 2014. Human Rho guanine nucleotide exchange factor 11 gene is associated with schizophrenia in a Japanese population. In Human psychopharmacology, 29, 552-8. doi:10.1002/hup.2435. https://pubmed.ncbi.nlm.nih.gov/25319871/
7. Fu, Mao, Sabra, Mona M, Damcott, Coleen, Baier, Leslie J, Shuldiner, Alan R. 2007. Evidence that Rho guanine nucleotide exchange factor 11 (ARHGEF11) on 1q21 is a type 2 diabetes susceptibility gene in the Old Order Amish. In Diabetes, 56, 1363-8. doi:. https://pubmed.ncbi.nlm.nih.gov/17369523/
8. Williams, Jan M, Johnson, Ashley C, Stelloh, Cary, Roman, Richard J, Garrett, Michael R. 2012. Genetic variants in Arhgef11 are associated with kidney injury in the Dahl salt-sensitive rat. In Hypertension (Dallas, Tex. : 1979), 60, 1157-68. doi:10.1161/HYPERTENSIONAHA.112.199240. https://pubmed.ncbi.nlm.nih.gov/22987919/