Dissociation of Rac1(GDP)·RhoGDI Complexes by the Cooperative Action of Anionic Liposomes Containing Phosphatidylinositol 3,4,5-Trisphosphate, Rac Guanine Nucleotide Exchange Factor, and GTP

Ugolev, Yelena; Berdichevsky, Yevgeny; Weinbaum, Carolyn; Pick, Edgar

doi:10.1074/jbc.m800734200

Cited by 47 publications

(41 citation statements)

References 67 publications

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“…This leads to activation of Rac1 and might explain the enhancement of neurite outgrowth when Kidins220 and RhoG are overexpressed. Trio and RhoG can bind to a variety of phospholipids (PIP x ) (Skowronek et al, 2004;Ugolev et al, 2008). (B)The different phenotypes generated by the expression of the ankyrin-rich Kidins220 1-402 domain and the full-length protein is likely to be due to their different localisations.…”

Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

Neubrand

Thomas

Schmidt

et al. 2010

Journal of Cell Science

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SummaryNeurite extension depends on extracellular signals that lead to changes in gene expression and rearrangement of the actin cytoskeleton. A factor that might orchestrate these signalling pathways with cytoskeletal elements is the integral membrane protein Kidins220/ARMS, a downstream target of neurotrophins. Here, we identified Trio, a RhoGEF for Rac1, RhoG and RhoA, which is involved in neurite outgrowth and axon guidance, as a binding partner of Kidins220. This interaction is direct and occurs between the N-terminus of Trio and the ankyrin repeats of Kidins220. Trio and Kidins220 colocalise at the tips of neurites in NGF-differentiated PC12 cells, where F-actin and Rac1 also accumulate. Expression of the ankyrin repeats of Kidins220 in PC12 cells inhibits NGF-dependent and Trioinduced neurite outgrowth. Similar results are seen in primary hippocampal neurons. Our data indicate that Kidins220 might localise Trio to specific membrane sites and regulate its activity, leading to Rac1 activation and neurite outgrowth.

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Section: Discussionmentioning

confidence: 99%

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

Neubrand

Thomas

Schmidt

et al. 2010

Journal of Cell Science

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“…However, the hypervariable (HV) region upstream of the CAAX sequence also modulates the subcellular localization of Rac1 (37,38). The affinity of the polybasic sequences in the HV region of Rac1 to different phospholipids has been extensively studied in vitro (39)(40)(41). Therefore, we wanted to investigate if the HV region along with the CAAX domain from Rac1 is sufficient to recapitulate the spatially regulated Rac1 recruitment in live cells.…”

Section: C-term Hypervariable Region Is Important For the Regulation mentioning

confidence: 99%

Single-molecule tracking of small GTPase Rac1 uncovers spatial regulation of membrane translocation and mechanism for polarized signaling

Das

Yin

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Polarized Rac1 signaling is a hallmark of many cellular functions, including cell adhesion, motility, and cell division. The two steps of Rac1 activation are its translocation to the plasma membrane and the exchange of nucleotide from GDP to GTP. It is, however, unclear whether these two processes are regulated independent of each other and what their respective roles are in polarization of Rac1 signaling. We designed a single-particle tracking (SPT) method to quantitatively analyze the kinetics of Rac1 membrane translocation in living cells. We found that the rate of Rac1 translocation was significantly elevated in protrusions during cell spreading on collagen. Furthermore, combining FRET sensor imaging with SPT measurements in the same cell, the recruitment of Rac1 was found to be polarized to an extent similar to that of the nucleotide exchange process. Statistical analysis of singlemolecule trajectories and optogenetic manipulation of membrane lipids revealed that Rac1 membrane translocation precedes nucleotide exchange, and is governed primarily by interactions with phospholipids, particularly PI(3,4,5)P 3 , instead of protein factors. Overall, the study highlights the significance of membrane translocation in spatial Rac1 signaling, which is in addition to the traditional view focusing primarily on GEF distribution and exchange reaction.super-resolution microscopy C ell polarization is critical for many biological processes, such as front−rear polarity during directed cell migration (chemotaxis, haptotaxis, wound healing, etc.), apical−basal polarity in epithelial cells, and axon specification in neuronal cells. The asymmetric distribution of signaling molecules, adhesion components, and cytoskeletal structures is important for the establishment of polarization. Among signaling proteins, the Rho family small GTPase Rac1 is ubiquitously required for cytoskeletal changes leading to a polarized morphology in many cells (1-4).Most small GTPases function as molecular switches, cycling between a GTP-bound active state and a GDP-bound inactive state. Activation of small GTPases typically requires guanine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP. Inactivation requires the inherent GTPase activity, enhanced by the GTPase Activating Proteins (GAPs) (5, 6). Thus, each Rac1 molecule continuously cycles between the active and inactive state during their intracellular existence.Besides the guanine nucleotide binding cycle, another cycle that governs Rac1 activity is the membrane/cytoplasm translocation cycle. Rac1 GTPase, as with many other small GTPases, is posttranslationally prenylated at its C terminus and is capable of binding to lipid bilayers (7,8). Under basal conditions, the majority of Rac1 localizes to the cytoplasm in complex with RhoGDI molecules, which block its interactions with GEFs and GAPs and its downstream effectors (9-12). To become active, Rac1 needs to translocate to the membrane and be free from RhoGDI binding, allowing for its activation by GEFs and its inter...

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“…S1P also induces tight-junction assembly that further strengthens the endothelial barrier ( Figure 3) (31,34,40). Because caged S1P-mediated barrier enhancement is Rac1-dependent (38), S1P may directly interact or bind with Rac1, and induce the dissociation of the Rho guanosine diphosphate (GDP) dissociation inhibitor (RhoGDI) from Rac1 for activation and redistribution to the cell periphery (41). This suggests that the action of S1P could be similar to that of another acidic phospholipid, phosphatidic acid (PA), generated by the phospholipase D signaling pathway, wherein PA acts as a membrane anchor of Rac1 by interacting with the polybasic motif in the carboxyl-terminal of Rac1, as shown in ovarian carcinoma-3 (OVCAR-3) cells (42).…”

Section: Mechanisms Of S1p-mediated Barrier Protectionmentioning

confidence: 99%

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

Natarajan

Dudek

Jacobson

et al. 2013

Am J Respir Cell Mol Biol

129

145

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Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P 1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.Keywords: sphingolipids; S1P receptors; sphingosine kinase; S1P lyase; sepsis Acute and subacute inflammatory lung injuries are common and devastating disorders resulting from insults such as sepsis, ventilator-induced lung injury, ischemia/reperfusion, hyperoxia, and radiation therapy for thoracic malignancies. Unfortunately, despite recent advances in our understanding of the mechanisms and pathophysiology of acute lung injury (ALI), mortality rates remain very high (30-50%) because of the dearth of specific therapies for the treatment of ALI (1, 2). The only therapy for radiation-induced pneumonitis is based on long-term treatment with a high dose of corticosteroids. However, it is encumbered by severe side effects and relatively low efficacy (3). Therefore, an urgent need exists for new mechanistic insights into the pathophysiology of ALI that are likely to reveal new potential therapeutic targets, discover novel biomarkers, and develop highly efficacious targeted therapies that will effectively reduce the morbidity and mortality associated with acute and subacute lung injury."Sphingosin," first described by J. L. W. Thudichum in 1884, derived its name from the Greek word "sphinx" meaning enigmatic, and it encompasses many compounds commonly referred to as "sphingoid bases" (4). Since thei...

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Dissociation of Rac1(GDP)·RhoGDI Complexes by the Cooperative Action of Anionic Liposomes Containing Phosphatidylinositol 3,4,5-Trisphosphate, Rac Guanine Nucleotide Exchange Factor, and GTP

Cited by 47 publications

References 67 publications

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio

Single-molecule tracking of small GTPase Rac1 uncovers spatial regulation of membrane translocation and mechanism for polarized signaling

Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

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