Role of the Vps9-domain protein RgfA inDictyosteliumchemotaxis and development

2013 ◽  
Vol 59 (1) ◽  
pp. 22-27
Author(s):  
Jeffrey A. Hadwiger
Keyword(s):  
Cell Growth ◽  
Heterologous Expression ◽  
Rab Proteins ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Genes Encoding ◽  
Redundant Functions ◽  
External Signals

Proteins with a Vps9 domain function as guanine nucleotide exchange factors for Rab proteins and can mediate the uptake of cell surface receptors or other molecules through endocytosis. However, genes encoding these proteins have not been previously studied in cells with robust chemotactic capabilities. Several genes encoding Vps9 domains were identified in the genome of Dictyostelium discoideum, and one of the genes, designated as rgfA (DDB_G0272038), was examined for functions in cell growth, development, and chemotaxis. The rgfA gene was expressed during vegetative growth and throughout development, but disruption of this gene resulted in no major alterations in cell growth, macropinocytosis, developmental morphology, or chemotactic movement. However, heterologous expression of RgfA resulted in a delay of developmental morphogenesis and impaired chemotaxis of cells to folate but did not affect macropinocytosis. These results suggest that RgfA might share redundant functions with other Dictyostelium Vps9-domain proteins and that heterologous expression of this protein can alter processes that depend on the reception of external signals.

scholarly journals Rab GTPases: master regulators that establish the secretory and endocytic pathways

2017 ◽  
Vol 28 (6) ◽  
pp. 712-715 ◽  
Author(s):  
Suzanne R. Pfeffer
Keyword(s):  
Membrane Trafficking ◽  
Membrane Microdomains ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Open Questions ◽  
Endocytic Pathways

Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. Such so-called Rab cascades have evolved to establish domains that contain unique Rab proteins and their cognate effectors, which drive all steps of membrane trafficking. These findings deserve much broader recognition by the biomedical research community and are highlighted here, along with open questions that require serious attention for full understanding of the molecular basis of Rab GTPase-regulated membrane trafficking in eukaryotic cells.

scholarly journals Focus on Cdc42 in Breast Cancer: New Insights, Target Therapy Development and Non-Coding RNAs

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 146 ◽  
Author(s):  
Yu Zhang ◽  
Jun Li ◽  
Xing-Ning Lai ◽  
Xue-Qiao Jiao ◽  
Jun-Ping Xiong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Malignant Tumors ◽  
Target Therapy ◽  
Nucleotide Exchange ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Non Coding Rnas ◽  
Guanosine Triphosphatase

Breast cancer is the most common malignant tumors in females. Although the conventional treatment has demonstrated a certain effect, some limitations still exist. The Rho guanosine triphosphatase (GTPase) Cdc42 (Cell division control protein 42 homolog) is often upregulated by some cell surface receptors and oncogenes in breast cancer. Cdc42 switches from inactive guanosine diphosphate (GDP)-bound to active GTP-bound though guanine-nucleotide-exchange factors (GEFs), results in activation of signaling cascades that regulate various cellular processes such as cytoskeletal changes, proliferation and polarity establishment. Targeting Cdc42 also provides a strategy for precise breast cancer therapy. In addition, Cdc42 is a potential target for several types of non-coding RNAs including microRNAs and lncRNAs. These non-coding RNAs is extensively involved in Cdc42-induced tumor processes, while many of them are aberrantly expressed. Here, we focus on the role of Cdc42 in cell morphogenesis, proliferation, motility, angiogenesis and survival, introduce the Cdc42-targeted non-coding RNAs, as well as present current development of effective Cdc42-targeted inhibitors in breast cancer.

The Ras binary switch: an ideal processor for decoding complex Ca2+ signals?

2003 ◽  
Vol 31 (5) ◽  
pp. 966-969 ◽  
Author(s):  
S.A. Walker ◽  
P.J. Lockyer ◽  
P.J. Cullen
Keyword(s):  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Intracellular Calcium Concentration ◽  
Nucleotide Exchange ◽  
Ras Proteins ◽  
Complex Calcium ◽  
Calcium Signals ◽  
Surface Receptors ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Activation of cell-surface receptors often leads to changes in intracellular calcium concentration ([Ca2+]i). Receptor-generated calcium transients are often seen as repetitive spikes of elevated intracellular calcium concentration ([Ca2+]i), whose frequency varies according to the amplitude of the receptor stimuli. This suggests a requirement for molecular decoders, capable of interpreting such complex calcium signals into the correct physiological response. Ras proteins are binary molecular switches controlling a plethora of cellular responses. Whether Ras is in its active GTP-bound, or inactive GDP-bound, form is determined by the activity of guanine nucleotide exchange factors (GEFs) and GTPase-activating protein (GAPs). Calcium-regulated GEFs and GAPs have been identified, some with an exquisite sensitivity to [Ca2+]i, implicating a potential role of complex calcium signals in regulating Ras.

scholarly journals The Rho-GEF PIX-1 directs assembly or stability of lateral attachment structures between muscle cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jasmine C. Moody ◽  
Hiroshi Qadota ◽  
April R. Reedy ◽  
C. Denise Okafor ◽  
Niveda Shanmugan ◽  
...  
Keyword(s):  
Muscle Cell ◽  
Muscle Cells ◽  
Cell Types ◽  
Nucleotide Exchange ◽  
C Elegans ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Attachment Structures ◽  
Genes Encoding ◽  
Rho Gef

Abstract PIX proteins are guanine nucleotide exchange factors (GEFs) that activate Rac and Cdc42, and are known to have numerous functions in various cell types. Here, we show that a PIX protein has an important function in muscle. From a genetic screen in C. elegans, we found that pix-1 is required for the assembly of integrin adhesion complexes (IACs) at borders between muscle cells, and is required for locomotion of the animal. A pix-1 null mutant has a reduced level of activated Rac in muscle. PIX-1 localizes to IACs at muscle cell boundaries, M-lines and dense bodies. Mutations in genes encoding proteins at known steps of the PIX signaling pathway show defects at muscle cell boundaries. A missense mutation in a highly conserved residue in the RacGEF domain results in normal levels of PIX-1 protein, but a reduced level of activated Rac in muscle, and abnormal IACs at muscle cell boundaries.

scholarly journals The Regulation of Rab GTPases by Phosphorylation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1340
Author(s):  
Lejia Xu ◽  
Yuki Nagai ◽  
Yotaro Kajihara ◽  
Genta Ito ◽  
Taisuke Tomita
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Effector Proteins ◽  
Regulatory Proteins ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.

Specific localization of Rabs at intracellular membranes

2012 ◽  
Vol 40 (6) ◽  
pp. 1421-1425 ◽  
Author(s):  
Julia Blümer ◽  
Yao-Wen Wu ◽  
Roger S. Goody ◽  
Aymelt Itzen
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Rab Proteins ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Intracellular Membranes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
C Terminus ◽  
Guanine Nucleotide Dissociation Inhibitor ◽  
Specific Localization

Despite over two decades of research, the mechanism of Rab targeting to specific intracellular membranes is still not completely understood. Present evidence suggests that the original hypothesis that the message for targeting resides solely in the hypervariable C-terminus is incorrect, and a second mechanism involving a GDF [GDI (guanine-nucleotide-dissociation inhibitor) displacement factor] to disrupt stable Rab–GDI complexes has only been shown to apply in one case, despite the need for targeting over 60 human Rab proteins. Evidence for the involvement of Rab–effector interactions has only been presented for a few cases or in a very specific context. There is mounting evidence that GEFs (guanine-nucleotide-exchange factors) are essential for membrane targeting, although contributions from additional factors are likely to be of importance, at least in specific cases.

scholarly journals The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1422
Author(s):  
Jero Vicente-Soler ◽  
Teresa Soto ◽  
Alejandro Franco ◽  
José Cansado ◽  
Marisa Madrid
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Model Organism ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Evolutionary Changes ◽  
Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

scholarly journals Involvement of the Switch 2 Domain of Ras in Its Interaction with Guanine Nucleotide Exchange Factors

1996 ◽  
Vol 271 (19) ◽  
pp. 11076-11082 ◽  
Author(s):  
Lawrence A. Quilliam ◽  
Mark M. Hisaka ◽  
Sheng Zhong ◽  
Amy Lowry ◽  
Raymond D. Mosteller ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

scholarly journals Essential Role of Vav Family Guanine Nucleotide Exchange Factors in EphA Receptor-Mediated Angiogenesis

2006 ◽  
Vol 26 (13) ◽  
pp. 4830-4842 ◽  
Author(s):  
Sonja G. Hunter ◽  
Guanglei Zhuang ◽  
Dana Brantley-Sieders ◽  
Wojciech Swat ◽  
Christopher W. Cowan ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rac1 Gtpase ◽  
Rho Family ◽  
Epha Receptor

ABSTRACT Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2−/− Vav3−/− mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.

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