Rho GTPases in hematopoiesis and hemopathies

Abstract

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.

Figure 1

Intracellular signaling model of Rho GTPases in receptor-initiated pathways. Most Rho GTPases cycle between the GDP-bound, inactive state and the GTP-bound, active state. The GTP binding and GTP hydrolysis cycle is tightly regulated by Rho guanine nucleotide exchange factors (GEFs), Rho GTPase-activating proteins (GAPs), and Rho GDIs (GDP dissociation inhibitors), which also control their intracellular localization patterns. On activation by cytokine, chemokine, growth factor, or adhesion molecules, the GTP-bound Rho GTPases can transiently interact with a large panel of effector proteins to transduce signals that affect cell cycle, survival, transcription, adhesion, and cytoskeleton machineries.

Figure 2

Role of Rho GTPases in HSC/P homing, engraftment, and mobilization. Rac1, Rac2, Cdc42, and Rho control different hematopoietic stem and progenitor cell (HSC/P) functions. Signals required for HSC self-renewal are mediated by Rho, Cdc42, and Rac1. Although Rac1 appears to be required for proliferation, Rac2 controls survival. Cdc42 is necessary for cell-cycle entry of quiescent (G₀) HSC/Ps in the bone marrow (BM) microenvironment, proliferation, and aging of HSC/Ps. Rac1 and Cdc42 control homing and interaction with the BM niche, whereas combined Rac1 and Rac2 activities and Cdc42 are necessary for the retention of HSC/Ps in the BM.

Figure 3

In erythrocytes that lack Rac1 and Rac2 GTPases, there is increased phosphorylation of adducin by protein kinase C, leading to decreased F-actin capping at the barbed ends, dissociation of spectrin from actin, and increased fragility of the RBC cytoskeleton.

Figure 4

Scheme of Rho GTPase involvements in lymphocyte development. Rac1 and Rac2 are important for common lymphoid progenitor (CLP) differentiation from hematopoietic stem cells (HSCs) in the BM. Rac1 and Rac2, as well as RhoH, regulate T-cell development in the thymus by affecting β-selection and positive selection. Rac2 is also required for Th1 differentiation in peripheral lymphoid tissues. Rac1, Rac2, and Cdc42 are critical for multiple stages of B-cell development in the spleen, whereas Rac2, Cdc42, and RhoG also regulate antibody production. DN indicates CD4⁻CD8⁻ double-negative thymocytes; DP, CD4⁺CD8⁺ double-positive thymocytes; SP, CD4⁺ or CD8⁺ single-positive T cells; Th, helper T cells; Tc, cytotoxic T cells; NFB, newly formed B cells; MZB, marginal zone B cells; and FOB, follicular B cells.

Figure 5

Phagocyte functions in response to bacterial infections. After sensing chemokines released by invading microorganism, leukocytes rapidly move toward the site of infection. This process involves initial changes in adhesive properties of the cells to the vessel endothelium followed by an extravasation step out of the blood vessel and directed migration into tissue. Once at the site of infection, cells phagocytize microbes and kill them by degranulation and reactive oxygen species (ROS) release.

Figure 6

A biochemical model of Rac GTPase involvement in hematopoietic cell transformation. Rac1 has unique as well as redundant roles with Rac2 and Rac3 as signal transducers in multiple oncogene or tumor suppressor gene–mediated leukemogenesis or lymphomagenesis, in addition to their physiologic roles in mediating receptor-stimulated signaling. They are required for p210 BCR-ABL–induced HSC transformation, and MLL-AF9–induced HSC/GMP transformation. Targeting of Rac GTPases has been suggested as a potential therapeutic means in the blood malignancies.

Figure 7

A summary of the known involvement of Rho GTPases in the regulation of hematopoiesis based on mouse gene–targeting studies. Cdc42, Rac1, Rac2, RhoH, RhoG, and RhoA are among the best understood Rho GTPase family members for which mouse gene–targeting models have been characterized in various blood lineages. LTR indicates long-term repopulating; and STR, short-term repopulating. Other abbreviations of various progenitors are described in the text.