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Ras Subfamily and Regulators in Human Disease and Repair

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 7551

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Special Issue Editors

Prof. Dr. Rolf Heumann

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Guest Editor

Department of Biochemistry II—Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, Ruhr-Universität Bochum, 44801 Bochum, Germany
Interests: neuronal protection; transgenic synRas mice; Ras and neuronal regeneration; Leucin-rich repeat kinase2 (LRRK2); functionalized nanoparticles; Nurr1; Parkinson
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Christian Herrmann

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Physical Chemistry I, Ruhr Universität Bochum, Bochum, Germany
Interests: thermodynamic and kinetic characterization of protein interactions; proteins in cellular signal transduction; molecular mechanism and function of human Guanylate Binding Proteins (GBP)

Special Issue Information

Dear Colleagues,

In this Special Issue we focus on the impact of Ras and Ras-like GTPase proteins on human disease and repair, including Rap, Rheb, Rhes, Ral, MRas, RasD, ERas, RRas, and others. The “on” and “off” states of Ras GTPases are regulated by interaction with guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), respectively. In addition, there is a family of proteins containing Ras binding (RB) or Ras association (RA) domains serving as effectors or signaling regulators. Signaling cross-talks between Ras-like proteins and other members of the superfamily, such as Rho or Rab, result from cross-activating mechanisms and overlapping specificities of GAPs or GEFs.

Deregulation of above-mentioned proteins and their signaling pathways due to mutation or modified expression is associated with a number of human diseases. Ras protein isoforms H-Ras, N-Ras, and K-Ras are mainly characterized by different C-terminal membrane anchoring mechanisms and mutations are found in various types of cancer. Moreover, there are cell type and cell lineage specific effects by Ras-like proteins implicating that developmental timing has a major role on the type of dysfunction. Germline mutations of Ras or its effectors result in RASopathies such as Costello syndrome or Noonan syndrome, causing cardiac and craniofacial abnormalities, hematologic/oncologic manifestations, and nervous system anomalies with intellectual deficits.

We believe that the impact of Ras and Ras-like proteins on brain cell functions such as neuronal survival, neuronal cell volume, synaptic transmission, synaptic connectivity, neuronal guidance, and myelination is rather underestimated. Ras and Ras-like proteins appear to be involved in neurodegenerative diseases i.e., Alzheimer’s, Parkinson’s and autism spectrum disorders. The therapeutic potential of Ras and Ras-like proteins as pharmacological targets or as agents counter-regulating the disease state by enhancement of tissue regeneration using novel strategies in magnetogenetics or optogenetics are just emerging. Manuscripts may cover either original data in a specialized field, short reviews or a comprehensive review e.g., bridging molecular and clinical perspectives. Contributions to any aspect discussed here are encouraged, as well as related topics not explicitly mentioned.

Prof. Dr. Rolf Heumann
Prof. Dr. Christian Herrmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Ras-like proteins
cancer
RASopathy
neurodegenerative diseases
GTPase activating proteins
guanine nucleotide exchange factors
dysfunction
synaptic transmission
neuronal regeneration
magneto protein therapy
optogenetics

Published Papers (2 papers)

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Research

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19 pages, 5398 KiB

Open AccessArticle

Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro

by David Wegrzyn, Christine Wegrzyn, Kerry Tedford, Klaus-Dieter Fischer and Andreas Faissner

Int. J. Mol. Sci. 2020, 21(3), 856; https://doi.org/10.3390/ijms21030856 - 28 Jan 2020

Cited by 2 | Viewed by 3069

Abstract

Vav proteins activate GTPases of the RhoA subfamily that regulate the cytoskeleton and are involved in adhesion, migration, differentiation, polarity and the cell cycle. While the importance of RhoA GTPases for neuronal morphology is undisputed, their regulation is less well understood. In this perspective, we studied the consequences of the deletion of Vav2, Vav3 and Vav2 and 3 (Vav2^−/−, Vav3^−/−, Vav2^−/−/3^−/−) for the development of embryonic hippocampal neurons in vitro. Using an indirect co-culture system of hippocampal neurons with primary wild-type (WT) cortical astrocytes, we analysed axonal and dendritic parameters, structural synapse numbers and the spontaneous network activity via immunocytochemistry and multielectrode array analysis (MEA). Here, we observed a higher process complexity in Vav3^−/−, but not in Vav2^−/− neurons after three and five days in vitro (DIV). Furthermore, an enhanced synapse formation was observed in Vav3^−/− after 14 days in culture. Remarkably, Vav2^−/−/3^−/− double knockout neurons did not display synergistic effects. Interestingly, these differences were transient and compensated after a cultivation period of 21 days. Network analysis revealed a diminished number of spontaneously occurring action potentials in Vav3^−/− neurons after 21 DIV. Based on these results, it appears that Vav3 participates in key events of neuronal differentiation. Full article

(This article belongs to the Special Issue Ras Subfamily and Regulators in Human Disease and Repair)

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Review

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14 pages, 643 KiB

Open AccessReview

SOS2 Comes to the Fore: Differential Functionalities in Physiology and Pathology

by Fernando C. Baltanás, Rósula García-Navas and Eugenio Santos

Int. J. Mol. Sci. 2021, 22(12), 6613; https://doi.org/10.3390/ijms22126613 - 21 Jun 2021

Cited by 14 | Viewed by 3586

Abstract

The SOS family of Ras-GEFs encompasses two highly homologous and widely expressed members, SOS1 and SOS2. Despite their similar structures and expression patterns, early studies of constitutive KO mice showing that SOS1-KO mutants were embryonic lethal while SOS2-KO mice were viable led to initially viewing SOS1 as the main Ras-GEF linking external stimuli to downstream RAS signaling, while obviating the functional significance of SOS2. Subsequently, different genetic and/or pharmacological ablation tools defined more precisely the functional specificity/redundancy of the SOS1/2 GEFs. Interestingly, the defective phenotypes observed in concomitantly ablated SOS1/2-DKO contexts are frequently much stronger than in single SOS1-KO scenarios and undetectable in single SOS2-KO cells, demonstrating functional redundancy between them and suggesting an ancillary role of SOS2 in the absence of SOS1. Preferential SOS1 role was also demonstrated in different RASopathies and tumors. Conversely, specific SOS2 functions, including a critical role in regulation of the RAS–PI3K/AKT signaling axis in keratinocytes and KRAS-driven tumor lines or in control of epidermal stem cell homeostasis, were also reported. Specific SOS2 mutations were also identified in some RASopathies and cancer forms. The relevance/specificity of the newly uncovered functional roles suggests that SOS2 should join SOS1 for consideration as a relevant biomarker/therapy target. Full article

(This article belongs to the Special Issue Ras Subfamily and Regulators in Human Disease and Repair)

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