scholarly journals Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1522 ◽  
Author(s):  
Daniel Abankwa ◽  
Alemayehu A. Gorfe
Keyword(s):  
Plasma Membrane ◽  
Structural Information ◽  
Pharmacological Intervention ◽  
Membrane Anchor ◽  
Specific Composition ◽  
Open Questions ◽  
Microscopy Data ◽  
New Research ◽  
Domain Reorientation ◽  
Dependent Type

Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanoclusters. We discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization while the whole Ras/RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

scholarly journals Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

2020 ◽  
Author(s):  
Daniel Abankwa ◽  
Alemayehu Gorfe
Keyword(s):  
Plasma Membrane ◽  
Structural Information ◽  
Pharmacological Intervention ◽  
Membrane Anchor ◽  
Specific Composition ◽  
Open Questions ◽  
Microscopy Data ◽  
New Research ◽  
Domain Reorientation ◽  
Dependent Type

Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we will review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanocluster. We will discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We will then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we will show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/ neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization, while the whole Ras/ RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including, whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

Towards a General Theory of Information

2018 ◽  
pp. 4459-4469
Author(s):  
Laura L. Pană
Keyword(s):  
Information Structure ◽  
Structural Information ◽  
Technical Information ◽  
Information Efficiency ◽  
Internal Information ◽  
New Research ◽  
Interdisciplinary Study ◽  
Information Aesthetics ◽  
Information Functional ◽  
Information Values

Contemporary society is an information society, based on Information Sciences and Information Technology. Technical information is therefore the most accessed and further promoted. This article aims to push toward completeness the study of information by analyzing the variety of information types and by presenting the hierarchy of information levels of existence. Specific features of natural, social and human information are highlighted. The internal information structure of distinct domains and levels of natural and social existence is explored. Information types such as structural information, systemic information, functional information or free information are characterized and defined, from various perspectives. An interdisciplinary study of information is thus accomplished, by using findings from several scientific and philosophical disciplines, from Information Epistemology or Information Aesthetics to Neuroinformatics and Neurorobotics. New research topics such as information values, information efficiency and information responsibility are proposed at the end of article.

scholarly journals Distinct Roles of N-Terminal Fatty Acid Acylation of the Salinity-Sensor Protein SOS3

2021 ◽  
Vol 12 ◽  
Author(s):  
Irene Villalta ◽  
Elena García ◽  
Dámaso Hornero-Mendez ◽  
Raúl Carranco ◽  
Carlos Tello ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Vascular Plants ◽  
Structural Information ◽  
Subcellular Targeting ◽  
Nuclear Trafficking ◽  
Sodium Efflux ◽  
Sos Pathway ◽  
Net Uptake ◽  
And Function ◽  
Salt Overly Sensitive

The Salt-Overly-Sensitive (SOS) pathway controls the net uptake of sodium by roots and the xylematic transfer to shoots in vascular plants. SOS3/CBL4 is a core component of the SOS pathway that senses calcium signaling of salinity stress to activate and recruit the protein kinase SOS2/CIPK24 to the plasma membrane to trigger sodium efflux by the Na/H exchanger SOS1/NHX7. However, despite the well-established function of SOS3 at the plasma membrane, SOS3 displays a nucleo-cytoplasmic distribution whose physiological meaning is not understood. Here, we show that the N-terminal part of SOS3 encodes structural information for dual acylation with myristic and palmitic fatty acids, each of which commands a different location and function of SOS3. N-myristoylation at glycine-2 is essential for plasma membrane association and recruiting SOS2 to activate SOS1, whereas S-acylation at cysteine-3 redirects SOS3 toward the nucleus. Moreover, a poly-lysine track in positions 7–11 that is unique to SOS3 among other Arabidopsis CBLs appears to be essential for the correct positioning of the SOS2-SOS3 complex at the plasma membrane for the activation of SOS1. The nuclear-localized SOS3 protein had limited bearing on the salt tolerance of Arabidopsis. These results are evidence of a novel S-acylation dependent nuclear trafficking mechanism that contrasts with alternative subcellular targeting of other CBLs by S-acylation.

scholarly journals Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function

2019 ◽  
Vol 2 (5) ◽  
pp. e201900431 ◽  
Author(s):  
Walaa E Kattan ◽  
Wei Chen ◽  
Xiaoping Ma ◽  
Tien Hung Lan ◽  
Dharini van der Hoeven ◽  
...  
Keyword(s):  
Biological Activity ◽  
Plasma Membrane ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Lipid Binding ◽  
Small Gtpase ◽  
Membrane Anchor ◽  
Normal Cells

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We, therefore, investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidyl-4-phosphate synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion significantly reduced proliferation and anchorage-independent growth of multiple KRAS-dependent cancer cell lines, and attenuated KRAS signaling in vivo. Similarly, functionally inhibiting ORP5 and ORP8 by inhibiting PI4KIIIα-mediated synthesis of phosphatidyl-4-phosphate at the PM selectively inhibited the growth of KRAS-dependent cancer cell lines over normal cells. Inhibiting KRAS function through regulating PM lipid PtdSer content may represent a viable strategy for KRAS-driven cancers.

scholarly journals Pathophysiology of ocular toxoplasmosis: Facts and open questions

2020 ◽  
Vol 14 (12) ◽  
pp. e0008905
Author(s):  
Valentin Greigert ◽  
Faiza Bittich-Fahmi ◽  
Alexander W. Pfaff
Keyword(s):  
Protozoan Parasite ◽  
Ocular Toxoplasmosis ◽  
Interleukin 17 ◽  
Type I ◽  
Parasite Control ◽  
Open Questions ◽  
Immune Pathways ◽  
Clinical Description ◽  
New Research

Infections with the protozoan parasite Toxoplasma gondii are frequent, but one of its main consequences, ocular toxoplasmosis (OT), remains poorly understood. While its clinical description has recently attracted more attention and publications, the underlying pathophysiological mechanisms are only sparsely elucidated, which is partly due to the inherent difficulties to establish relevant animal models. Furthermore, the particularities of the ocular environment explain why the abundant knowledge on systemic toxoplasmosis cannot be just transferred to the ocular situation. However, studies undertaken in mouse models have revealed a central role of interferon gamma (IFNγ) and, more surprisingly, interleukin 17 (IL17), in ocular pathology and parasite control. These studies also show the importance of the genetic background of the infective Toxoplasma strain. Indeed, infections due to exotic strains show a completely different pathophysiology, which translates in a different clinical outcome. These elements should lead to more individualized therapy. Furthermore, the recent advance in understanding the immune response during OT paved the way to new research leads, involving immune pathways poorly studied in this particular setting, such as type I and type III interferons. In any case, deeper knowledge of the mechanisms of this pathology is needed to establish new, more targeted treatment schemes.

scholarly journals Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thomas Blom ◽  
Rutger Meinsma ◽  
Franca di Summa ◽  
Emile van den Akker ◽  
André B. P. van Kuilenburg ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Transport ◽  
Serotonin Transporter ◽  
Hek293 Cells ◽  
Pharmacological Intervention ◽  
Mibg Uptake ◽  
Hematopoietic Stem ◽  
Specific Uptake ◽  
Mibg Therapy

Abstract Background The therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake. Methods Peripheral blood CD34+ cells were differentiated to human megakaryocytic cells using a standardized culture protocol. Prior to [3H]serotonin and [125I]MIBG uptake experiments, the differentiation status of megakaryocyte cultures was assessed by flow cytometry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess SERT and NET (norepinephrine transporter) mRNA expression. On day 10 of differentiation, [3H]serotonin and [125I]MIBG uptake assays were conducted. Part of the samples were co-incubated with the SSRI citalopram to assess SERT-specific uptake. HEK293 cells transfected with SERT, NET, and empty vector served as controls. Results In vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG. After 10 days of differentiation, megakaryocytic cell culture batches from three different hematopoietic stem and progenitor cell donors showed on average 9.2 ± 2.4 nmol of MIBG uptake per milligram protein per hour after incubation with 10–7 M MIBG (range: 6.6 ± 1.0 to 11.2 ± 1.0 nmol/mg/h). Co-incubation with the SSRI citalopram led to a significant reduction (30.1%—41.5%) in MIBG uptake, implying SERT-specific uptake of MIBG. A strong correlation between the number of mature megakaryocytes and SERT-specific MIBG uptake was observed. Conclusion Our study demonstrates that human megakaryocytes cultured in vitro are capable of MIBG uptake. Moreover, the SSRI citalopram selectively inhibits MIBG uptake via the serotonin transporter. The concomitant administration of citalopram to neuroblastoma patients during [131I]MIBG therapy might be a promising strategy to prevent the onset of thrombocytopenia.

scholarly journals Targeting of the Sendai Virus C Protein to the Plasma Membrane via a Peptide-Only Membrane Anchor

2007 ◽  
Vol 81 (7) ◽  
pp. 3187-3197 ◽  
Author(s):  
Jean-Baptiste Marq ◽  
Albert Brini ◽  
Daniel Kolakofsky ◽  
Dominique Garcin
Keyword(s):  
Plasma Membrane ◽  
Sendai Virus ◽  
Intracellular Localization ◽  
Membrane Targeting ◽  
Membrane Anchor ◽  
C Protein ◽  
Cellular Antiviral Response ◽  
Α Helix ◽  
Virus C ◽  
Cellular Compartments

ABSTRACT Several cellular proteins are synthesized in the cytosol on free ribosomes and then associate with membranes due to the presence of short peptide sequences. These membrane-targeting sequences contain sites to which lipid chains are attached, which help direct the protein to a particular membrane domain and anchor it firmly in the bilayer. The intracellular concentration of these proteins in particular cellular compartments, where their interacting partners are also concentrated, is essential to their function. This paper reports that the apparently unmodified N-terminal sequence of the Sendai virus C protein (MPSFL KK IL K L R G RR . . .; letters in italics represent hydrophobic residues; underlined letters represent basic residues, which has a strong propensity to form an amphipathic α-helix in a hydrophobic environment) also function as a membrane targeting signal and membrane anchor. Moreover, the intracellular localization of the C protein at the plasma membrane is essential for inducing the interferon-independent phosphorylation of Stat1 as part of the viral program to prevent the cellular antiviral response.

scholarly journals Differential targeting of two glucose transporters from Leishmania enriettii is mediated by an NH2-terminal domain.

1995 ◽  
Vol 128 (4) ◽  
pp. 499-508 ◽  
Author(s):  
R C Piper ◽  
X Xu ◽  
D G Russell ◽  
B M Little ◽  
S M Landfear
Keyword(s):  
Plasma Membrane ◽  
Life Cycle ◽  
Glucose Transporter ◽  
Structural Information ◽  
Glucose Transporters ◽  
Insect Vector ◽  
Flagellar Pocket ◽  
Confocal Immunofluorescence Microscopy ◽  
Modular Structures ◽  
Hydrophilic Domain

Leishmania are parasitic protozoa with two major stages in their life cycle: flagellated promastigotes that live in the gut of the insect vector and nonflagellated amastigotes that live inside the lysosomes of the vertebrate host macrophages. The Pro-1 glucose transporter of L. enriettii exists as two isoforms, iso-1 and iso-2, which are both expressed primarily in the promastigote stage of the life cycle. These two isoforms constitute modular structures: they differ exclusively and extensively in their NH2-terminal hydrophilic domains, but the remainder of each isoform sequence is identical to that of the other. We have localized these glucose transporters within promastigotes by two approaches. In the first method, we have raised a polyclonal antibody against the COOH-terminal hydrophilic domain shared by both iso-1 and iso-2, and we have used this antibody to detect the transporters by confocal immunofluorescence microscopy and immunoelectron microscopy. The staining observed with this antibody occurs primarily on the plasma membrane and the membrane of the flagellar pocket, but there is also light staining on the flagellum. We have also localized each isoform separately by introducing an epitope tag into each protein sequence. These experiments demonstrate that iso-1, the minor isoform, resides primarily on the flagellar membrane, while iso-2, the major isoform, is located on the plasma membrane and the flagellar pocket. Hence, each isoform is differentially sorted, and the structural information for targeting each transporter isoform to its correct membrane address resides within the NH2-terminal hydrophilic domain.

scholarly journals Plant Vascular Tissues—Connecting Tissue Comes in All Shapes

Plants ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 109 ◽  
Author(s):  
Eva Hellmann ◽  
Donghwi Ko ◽  
Raili Ruonala ◽  
Ykä Helariutta
Keyword(s):  
Arabidopsis Thaliana ◽  
Building Material ◽  
Food Source ◽  
Vascular Tissues ◽  
Open Questions ◽  
Storage Organs ◽  
The Status ◽  
Important Field ◽  
New Research ◽  
And Storage

For centuries, humans have grown and used structures based on vascular tissues in plants. One could imagine that life would have developed differently without wood as a resource for building material, paper, heating energy, or fuel and without edible tubers as a food source. In this review, we will summarise the status of research on Arabidopsis thaliana vascular development and subsequently focus on how this knowledge has been applied and expanded in research on the wood of trees and storage organs of crop plants. We will conclude with an outlook on interesting open questions and exciting new research opportunities in this growing and important field.

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