Rho family GTPases: Making it to the third dimension

Riching, Kristin M.; Keely, Patricia J.

doi:10.1016/j.biocel.2014.11.007

Cited by 17 publications

(15 citation statements)

References 43 publications

(57 reference statements)

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“…Obviously, studies of cells cultured on stiff 2D substrates paved the way to our understanding of cell migration, but the analysis of 3D models is now needed to uncover the role of microtubules in cell motility in a more-physiological context. In fact, compared to F-actin and its regulators, the contribution of microtubules to 3D cell motility appears underexplored Riching and Keely, 2015). Here, we review the current body of data that establishes a clear link between microtubules and cell motility in 3D by focusing mostly on soft 3D matrices, and discuss similarities and differences with the results from classic 2D models when available.…”

Section: Introductionmentioning

confidence: 95%

Microtubules in 3D cell motility

Bouchet

Akhmanova

2017

Journal of Cell Science

102

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Three-dimensional (3D) cell motility underlies essential processes, such as embryonic development, tissue repair and immune surveillance, and is involved in cancer progression. Although the cytoskeleton is a well-studied regulator of cell migration, most of what we know about its functions originates from studies conducted in twodimensional (2D) cultures. This research established that the microtubule network mediates polarized trafficking and signaling that are crucial for cell shape and movement in 2D. In parallel, developments in light microscopy and 3D cell culture systems progressively allowed to investigate cytoskeletal functions in more physiologically relevant settings. Interestingly, several studies have demonstrated that microtubule involvement in cell morphogenesis and motility can differ in 2D and 3D environments. In this Commentary, we discuss these differences and their relevance for the understanding the role of microtubules in cell migration in vivo. We also provide an overview of microtubule functions that were shown to control cell shape and motility in 3D matrices and discuss how they can be investigated further by using physiologically relevant models.

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Section: Introductionmentioning

confidence: 95%

Microtubules in 3D cell motility

Bouchet

Akhmanova

2017

Journal of Cell Science

102

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“…For example, during 2-dimensional cell migration, Rac1 and Cdc42 promote the actin-driven protrusions at the cell leading edge, whereas RhoA controls the actomyosin contraction at the cell body and rear. In 3-dimensional conditions, cells adapt different modes of migration dependent on spatial and temporal activation of Rho GTPases in response to the environmental cues [11,12] . RhoA mediates stress fiber formation mainly via Rho-kinase (ROCK) and mammalian diaphanous (mDia), while Rac1 and Cdc42 regulate actin re-organization by signaling via p21-activated kinases (Pak) or IQ-domain GTPase-activating protein (IQGAP).…”

Section: Introductionmentioning

confidence: 99%

Approaches of targeting Rho GTPases in cancer drug discovery

Lin

Zheng

2015

Expert Opinion on Drug Discovery

105

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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“…Arf6, an Arf (ADP-ribosylation factor) family member, is involved in endocytic pathways, endosomal recycling, cell migration, exocytosis, actin reorganization, plasma membrane reorganization, and cytokinesis (2). RhoA belongs to the Rho (Ras homologous) family, which primarily regulates cell shape, polarity, and motility by inducing stress fibers in cells that provides intracellular contractility (3)(4)(5)(6). In addition, Arf6 plays a role in cancer cell invasion, and RhoA regulates cancer cell morphology and migration (7,8).…”

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confidence: 99%

Structural Basis for the Specific Recognition of RhoA by the Dual GTPase-activating Protein ARAP3

Bao

Wang

et al. 2016

Journal of Biological Chemistry

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ARAP3 (Arf-GAP with Rho-GAP domain, ANK repeat, and PH domain-containing protein 3) is unique for its dual specificity GAPs (GTPase-activating protein) activity for Arf6 (ADPribosylation factor 6) and RhoA (Ras homolog gene family member A) regulated by phosphatidylinositol 3,4,5-trisphosphate and a small GTPase Rap1-GTP and is involved in regulation of cell shape and adhesion. However, the molecular interface between the ARAP3-RhoGAP domain and RhoA is unknown, as is the substrates specificity of the RhoGAP domain. In this study, we solved the crystal structure of RhoA in complex with the RhoGAP domain of ARAP3. The structure of the complex presented a clear interface between the RhoGAP domain and RhoA. By analyzing the crystal structure and in combination with in vitro GTPase activity assays and isothermal titration calorimetry experiments, we identified the crucial residues affecting RhoGAP activity and substrates specificity among RhoA, Rac1 (Ras-related C3 botulinum toxin substrate 1), and Cdc42 (cell division control protein 42 homolog).

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Rho family GTPases: Making it to the third dimension

Cited by 17 publications

References 43 publications

Microtubules in 3D cell motility

Microtubules in 3D cell motility

Approaches of targeting Rho GTPases in cancer drug discovery

Structural Basis for the Specific Recognition of RhoA by the Dual GTPase-activating Protein ARAP3

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