Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, OH 45229, USA.
Blood. 2010 Feb 4;115(5):936-47. doi: 10.1182/blood-2009-09-198127. Epub 2009 Nov 24.
Rho family GTPases are intracellular signaling proteins regulating multiple pathways involved in cell actomyosin organization, adhesion, and proliferation. Our knowledge of their cellular functions comes mostly from previous biochemical studies that used mutant overexpression approaches in various clonal cell lines. Recent progress in understanding Rho GTPase functions in blood cell development and regulation by gene targeting of individual Rho GTPases in mice has allowed a genetic understanding of their physiologic roles in hematopoietic progenitors and mature lineages. In particular, mouse gene-targeting studies have provided convincing evidence that individual members of the Rho GTPase family are essential regulators of cell type-specific functions and stimuli-specific pathways in regulating hematopoietic stem cell interaction with bone marrow niche, erythropoiesis, and red blood cell actin dynamics, phagocyte migration and killing, and T- and B-cell maturation. In addition, deregulation of Rho GTPase family members has been associated with multiple human hematologic diseases such as neutrophil dysfunction, leukemia, and Fanconi anemia, raising the possibility that Rho GTPases and downstream signaling pathways are of therapeutic value. In this review we discuss recent genetic studies of Rho GTPases in hematopoiesis and several blood lineages and the implications of Rho GTPase signaling in hematologic malignancies, immune pathology. and anemia.
Rho 家族 GTPases 是细胞内信号蛋白，调节参与细胞肌动球蛋白组织、黏附和增殖的多种途径。我们对其细胞功能的了解主要来自以前的生化研究，这些研究使用各种克隆细胞系中的突变体过表达方法。最近在理解 Rho GTPase 在血细胞发育中的功能以及通过基因靶向个别 Rho GTPase 在小鼠中的作用方面的进展，使我们能够从遗传学上理解它们在造血祖细胞和成熟谱系中的生理作用。特别是，小鼠基因靶向研究提供了令人信服的证据，证明 Rho GTPase 家族的各个成员是调节造血干细胞与骨髓龛相互作用、红细胞生成和红细胞肌动蛋白动力学、吞噬细胞迁移和杀伤以及 T 细胞和 B 细胞成熟的特定细胞类型功能和特定刺激途径的必需调节剂。此外，Rho GTPase 家族成员的失调与多种人类血液疾病有关，如中性粒细胞功能障碍、白血病和范可尼贫血，这表明 Rho GTPases 和下游信号通路具有治疗价值。在这篇综述中，我们讨论了 Rho GTPase 在造血和几种血液谱系中的遗传研究，以及 Rho GTPase 信号在血液恶性肿瘤、免疫病理学和贫血中的意义。
