Cell Type-specific Signaling Function of RhoA GTPase: Lessons from Mouse Gene Targeting

Zhou, Xuan; Zheng, Yi

doi:10.1074/jbc.r113.515486

Cited by 46 publications

(41 citation statements)

References 92 publications

(97 reference statements)

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“…The results obtained suggest a high degree of independence between these pathways, although it is not complete because at least the chemotaxis and the survival modules are connected, with the former controlling modestly the latter. Albeit each one of the three pathways can regulate several functions in different contexts (43,44,52,62), CCR7 seems to select only one activity in maDCs. The molecular mechanisms supporting the independence and biased functionality of these pathways are not known.…”

Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells

Rodrı́guez-Fernández

Criado‐García

2020

Front. Immunol.

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Chemotaxis is a molecular mechanism that confers leukocytes the ability to detect gradients of chemoattractants. Chemokine receptors are well-known regulators of chemotaxis in leukocytes; however, they can regulate several other activities in these cells. This information has been often neglected, probably due to the paramount role of chemotaxis in the immune system and in biology. Therefore, the experimental data available on the mechanisms used by chemokine receptors to regulate other functions of leukocytes is sparse. The results obtained in the study of the chemokine receptor CCR7 in dendritic cells (DCs) provide interesting information on this issue. CCR7 guides the DCs from the peripheral tissues to the lymph nodes, where these cells control T cell activation. CCR7 can regulate DC chemotaxis, survival, migratory speed, cytoarchitecture, and endocytosis. Biochemical and functional analyses show: first, that CCR7 uses in DCs the PI3K/Akt pathway to control survival, the MAPK pathway to control chemotaxis, and the RhoA pathways to regulate actin dynamics, which in turn controls migratory speed, cytoarchitecture, and endocytosis; second, that these three signaling pathways behave as modules with a high degree of independence; and third, that although each one of these routes can regulate several functions in different settings, CCR7 promotes in DCs a functional bias in each pathway. The data uncover an interesting mechanism used by CCR7 to regulate the DCs, entailing multifunctional signaling pathways organized in modules with biased functionality. A similar mechanism could be used by other chemoattractant receptors to regulate the functions of leukocytes.

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Section: Discussionmentioning

confidence: 99%

The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells

Rodrı́guez-Fernández

Criado‐García

2020

Front. Immunol.

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“…More recent genetic mouse models targeting individual Rho GTPases have provided convincing evidence for their physiological roles. Direct targeting of RhoA, Rac1, or Cdc42 is embryonic lethal, so a variety of tissue-specific conditional knockout mouse models have been generated (reviewed in [24-26] ).…”

Section: Rho Gtpase Signaling Pathways and Cancermentioning

confidence: 99%

Approaches of targeting Rho GTPases in cancer drug discovery

Lin

Zheng

2015

Expert Opinion on Drug Discovery

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107

101

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Introduction Rho GTPases are master regulators of actomyosin structure and dynamics and play pivotal roles in a variety of cellular processes including cell morphology, gene transcription, cell cycle progression and cell adhesion. Because aberrant Rho GTPase signaling activities are widely associated with human cancer, key components of Rho GTPase signaling pathways have attracted increasing interest as potential therapeutic targets. Similar to Ras, Rho GTPases themselves were, until recently, deemed “undruggable” because of structure-function considerations. Several approaches to interfere with Rho GTPase signaling have been explored and show promise as new ways for tackling cancer cells. Areas covered This review focuses on the recent progress in targeting the signaling activities of three prototypical Rho GTPases, i.e. RhoA, Rac1, and Cdc42. The authors describe the involvement of these Rho GTPases, their key regulators and effectors in cancer. Furthermore, the authors discuss the current approaches for rationally targeting aberrant Rho GTPases along their signaling cascades, upstream and downstream of Rho GTPases and posttranslational modifications at a molecular level. Expert opinion To date, while no clinically effective drugs targeting Rho GTPase signaling for cancer treatment are available, tool compounds and lead drugs that pharmacologically inhibit Rho GTPase pathways have shown promise. Small molecule inhibitors targeting Rho GTPase signaling may add new treatment options for future precision cancer therapy, particularly in combination with other anti-cancer agents.

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“…Evaluation of these pathways in vivo has been hampered by the fact that mice with constitutional deletion of RhoA could not be created because of very early embryonic lethality. 13,14 In this study, we investigate the role of RhoA in vivo in the erythroid lineage using a Cre-lox recombination system in which Cre-recombinase expression is controlled by the erythropoietin receptor (EpoR) promoter, thereby resulting in erythroid-specific deletion of the floxed RhoA gene. 15 We found that RhoA is essential for cytokinesis in both primitive and definitive erythroid lineages.…”

Section: Introductionmentioning

confidence: 99%

Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

Konstantinidis

Giger

Risinger

et al. 2015

Blood

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Cell Type-specific Signaling Function of RhoA GTPase: Lessons from Mouse Gene Targeting

Cited by 46 publications

References 92 publications

The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells

The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells

Approaches of targeting Rho GTPases in cancer drug discovery

Cytokinesis failure in RhoA-deficient mouse erythroblasts involves actomyosin and midbody dysregulation and triggers p53 activation

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