Amgen Inc, South San Francisco, CA, USA.
Adv Exp Med Biol. 2012;728:195-213. doi: 10.1007/978-1-4614-0887-1_13.
FGF19 differs from the classical FGFs in that it has a much-reduced heparan sulfate proteoglycan binding affinity that allows it to act as endocrine hormone. Although FGF19 regulates several different metabolic activities, it still activates downstream signaling pathways through FGF receptors, in a similar manner to that seen in classical FGFs. Aberrant FGF signaling has been implicated in tumor development, and mouse models have confirmed that FGF19 has the potential to induce hepatocellular carcinoma. Treatment with anti-FGF19 antibody suppressed tumor progression in both FGF19 transgenic mice and colon cancer cell xenograft models. FGFR4, the predominant FGF receptor expressed in the liver, may play an important role in FGF19-mediated tumorigenesis. This review reports the current advances in understanding the structure-function relationship between FGF19 and its interactions with FGFRs, its physiological activities, and its differences from FGF21. The review also discusses strategies to separate the mitogenic and metabolic activities for the development of potential therapeutic molecules based on FGF19.
FGF19 与经典的 FGF 不同，它与硫酸乙酰肝素蛋白聚糖的结合亲和力大大降低，使其能够作为内分泌激素发挥作用。虽然 FGF19 调节多种不同的代谢活性，但它仍然通过 FGF 受体激活下游信号通路，这与经典 FGF 中观察到的方式相似。异常的 FGF 信号已被牵连到肿瘤的发展中，并且小鼠模型已证实 FGF19 具有诱导肝细胞癌的潜力。用抗 FGF19 抗体治疗可抑制 FGF19 转基因小鼠和结肠癌细胞异种移植模型中的肿瘤进展。FGFR4 是肝脏中表达的主要 FGF 受体，可能在 FGF19 介导的肿瘤发生中发挥重要作用。本综述报告了目前在理解 FGF19 与其与 FGFRs 的相互作用之间的结构-功能关系、其生理活性以及它与 FGF21 的差异方面的最新进展。该综述还讨论了基于 FGF19 分离有丝分裂和代谢活性的策略，以开发潜在的治疗分子。
