Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University , Lund , Sweden ; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University , Lund , Sweden ; and Division of Oncology, Skåne University Hospital , Lund , Sweden.
Physiol Rev. 2019 Jul 1;99(3):1433-1466. doi: 10.1152/physrev.00029.2018.
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.
FMS 样酪氨酸激酶 3（FLT3）是一种受体酪氨酸激酶，几乎仅在造血细胞中表达。其配体，FLT3 配体（FL），诱导其内在酪氨酸激酶活性的二聚化和激活。FLT3 的激活导致其自身磷酸化，并启动几个信号转导级联反应。信号通过信号转导分子与 FLT3 内源性区域中特定磷酸化的酪氨酸残基结合，募集到激活的 FLT3 上，从而启动信号。FLT3 的激活介导造血祖细胞的存活、增殖和分化。它与其他几种细胞因子协同作用，以促进其生物学效应。FLT3 活性失调与多种疾病有关，在急性髓系白血病中最为明显，大约三分之一的患者携带激活的 FLT3 突变体，这种突变体驱动疾病并与预后不良相关。FLT3 的过度活跃也与自身免疫性疾病有关，如类风湿关节炎。观察到 FLT3 的功能获得性突变可以促进白血病发生，这刺激了针对该受体的抑制剂的开发。其中许多抑制剂正在临床试验中，有些已经获得临床应用批准。然而，对这些抑制剂的获得性耐药是常见的问题，此外，只有一部分患者对这些选择性治疗有反应。这篇综述总结了我们目前对 FLT3 信号在正常和病理条件下的结构和功能方面的认识，并讨论了未来在利用这些途径的靶向抑制治疗患者方面的挑战。
