Table of Contents

Volume 2, Issue 1

  January/February 2011

  Pages 1 - 61

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Scientific dialogue in the electronic age

Michael J. Williams
Page 1
http://dx.doi.org/10.4161/sgtp.2.1.15644
Abstract | PDF




Open Access Article

In this issue of Small GTPases

Elaine L. Ellerton
Pages 2 - 3
http://dx.doi.org/10.4161/sgtp.2.1.15556
Abstract | PDF







RESEARCH PAPERS

Open Access Article

Evolution of the Ras-like small GTPases and their regulators

Teunis J.P. van Dam, Johannes Bos and Berend Snel
Pages 4 - 16
http://dx.doi.org/10.4161/sgtp.2.1.15113
Abstract | PDF

Small GTPases are molecular switches at the hub of many signaling pathways and the expansion of this protein family is interwoven with the origin of unique eukaryotic cell features. We have previously reported on the evolution of CDC25 Homology Domain containing proteins, which act as guanine nucleotide exchange factors (GEFs) for Ras-like proteins. We now report on the evolution of both the Ras-like small GTPases as well as the GTPase activating proteins (GAPs) for Ras-like small GTPases. We performed an in depth phylogenetic analysis in 64 genomes of diverse eukaryotic species. These analyses revealed that multiple ancestral Ras-like GTPases and GAPs were already present in the Last Eukaryotic Common Ancestor (LECA), compatible with the presence of RasGEFs in LECA. Furthermore, we endeavor to reconstruct in which order the different Ras-like GTPases diverged from each other. We identified striking differences between the expansion of the various types of Ras-like GTPases and their respective GAPs and GEFs. Altogether, our analysis forms an extensive evolutionary framework for Ras-like signaling pathways and provides specific predictions for molecular biologists and biochemists.

Open Access Article

Rho family GTPase Chp/RhoV induces PC12 apoptotic cell death via JNK activation

Mikhail V. Shepelev, Jonathan Chernoff and Igor V. Korobko
Pages 17 - 26
http://dx.doi.org/10.4161/sgtp.2.1.15229
Abstract | PDF

Rho GTPases regulate numerous cellular processes including apoptosis. Chp/RhoV is an atypical Rho GTPase which functions are poorly understood. Here we investigated the role of Chp in regulation of cell viability using PC12 cells with inducible expression of Chp as a model. We found that expression of Chp results in apoptosis in PC12 cells. Chp-induced apoptosis was accompanied by activation of JNK signaling and both death receptor-mediated and mitochondrial apoptotic pathways as justified by caspase-8 and caspase-9 activation, respectively. Moreover, inhibition of JNK by SP600125 rescued PC12 cells from Chp-triggered cell death and attenuated activation of caspases-9 and -3/7 suggesting that activation of JNK mediates pro-apoptotic effect of Chp. Expression of Chp resulted in increased phosphorylation of c-Jun in PC12 cells, and Chp expression in HEK293 cells up-regulated AP-1-dependent transcription in a JNK-dependent manner. Together results of our study reveal the role of Chp GTPase as a putative regulator of JNK-dependent apoptotic death in PC12 cells, similarly to previously described pro-apoptotic activity of the related Cdc42 and Rac1 GTPases.




EXTRA VIEWS

Open Access Article

GTP-dependent scaffold formation in the GTPase of Immunity-Associated Protein family

David Schwefel and Oliver Daumke
Pages 27 - 30
http://dx.doi.org/10.4161/sgtp.2.1.14938
Abstract | PDF

GTPases of Immunity-Associated Proteins (GIMAPs) are a family of guanine nucleotide binding (G) proteins which are implicated in the regulation of apoptosis in lymphocytes. GIMAPs are composed of an amino-terminal G domain and carboxy-terminal extensions of varying size. Our recent biochemical and structural analysis of a representative GIMAP family member, GIMAP2, revealed the molecular basis of GTP-dependent oligomerization which involves two interfaces in the G domain. Whereas the amphipathic helix α7 in the C-terminal extension closely folds against the G domain in the GDP-bound state, it might be released in the GTP-bound state to assemble interaction partners. We also showed that the GIMAP2 oligomer functions at the surface of lipid droplets in a Jurkat T cell line. Here, we review our recent work and discuss the GIMAP2 oligomer as a GTP-dependent protein scaffold at the surface of lipid droplets controlling apoptosis.

Open Access Article

Gimap3: A foot-in-the-door to tissue-specific regulation of mitochondrial DNA genetics

Riikka Jokinen, Heidi Junnila and Brendan J. Battersby
Pages 31 - 35
http://dx.doi.org/10.4161/sgtp.2.1.14937
Abstract | PDF

Mitochondrial DNA (mtDNA) is a multi-copy genome encoding for proteins essential for aerobic energy metabolism. Mutations in mtDNA can lead to a variety of human diseases, from mild metabolic syndromes to severe fatal encephalomyopathies. Most mtDNA mutations co-exist with wild type genomes in a state known as heteroplasmy. The segregation of these pathogenic mutants is tissue and mutation specific, and a key determinant in the onset and severity of human mitochondrial disorders. We used a forward genetic approach in mice to identify and demonstrate that Gimap3 (GTPase of immunity associated protein) is a key regulator of mtDNA segregation in leukocytes. The Gimap gene cluster is found only in vertebrates and appear to be a class of nucleotide-dependent dimerization GTPases. Gimap3 is a membrane-anchored GTPase with a critical role in T cell development. Here, we summarize our genetic findings and postulate how Gimap3 might regulate mtDNA genetics.


Open Access Article

Regulation of cell adhesion and migration in cortical neurons: Not only Rho but also Rab family small GTPases

Takeshi Kawauchi
Pages 36 - 40
http://dx.doi.org/10.4161/sgtp.2.1.15001
Abstract | PDF

Accumulating evidence indicate that Rho family small GTPases, including RhoA, Rac1 and Cdc42, control cytoskeletal organization and cell adhesion, and thereby cell migration in vitro and in vivo. Recently, the involvement of other small GTPases, such as Rab and Arf family proteins in cell migration has also been evaluated. Rab5, Rab11 and Rab7, which regulate endocytosis, recycling and lysosomal degradation pathways, respectively, are shown to have essential roles in the migration of immature neurons during the development of cerebral cortex in vivo. These Rab proteins control distinct steps of neuronal migration through the regulation of N-cadherin-mediated cell adhesion. In this extra view paper, I will discuss the functions of Rho and Rab family small GTPases in cell migration with particular focus on the migrating neurons in the developing cerebral cortex.

Open Access Article

C/EBPbeta’s role in determining Ras-induced senescence or transformation

Allison A. Atwood and Linda Sealy
Pages 41 - 46
http://dx.doi.org/10.4161/sgtp.2.1.15038
Abstract | PDF

Introduction of activated Ras into normal cells leads to senescence, a tumor suppressive mechanism, whereas expression of this oncogene in many immortalized cell lines leads to transformation. Studying the signaling differences in cells that undergo Ras-induced senescence versus Ras transformation may shed light on potential therapeutic targets in the treatment of cancer. C/EBPbeta is a transcription factor necessary for both Ras-induced senescence and Ras transformation. Three isoforms of this transcription factor exist due to alternative translation initation at three in frame ATGs. C/EBPbeta1 is the isoform responsible for oncogene-induced senescence, and this isoform is degraded by the proteosome during Ras transformation. Phosphorylation of C/EBPbeta1 on Thr235 by Cdk2 is necessary, but not sufficient, for degradation of C/EBPbeta1. Proteasomal degradation of C/EBPbeta1 may represent a mechanism to evade senescence. In contrast, C/EBPbeta2 is expressed in breast cancer cells and is involved in proliferation, supporting a role for this isoform in Ras transformation. We propose here that one potential signaling difference in Ras-induced senescence versus Ras transformation is that Ras signals through different C/EBPbeta isoforms (C/EBPbeta1 versus C/EBPbeta2) during these processes.

Open Access Article

“RACK”-ing up the effectors: Receptor for activated C kinase acts downstream of Rac GTPase signaling in growth cone outgrowth

Rafael S. Demarco and Erik A. Lundquist
Pages 47 - 50
http://dx.doi.org/10.4161/sgtp.2.1.15062
Abstract | PDF




Open Access Article

Vimentin: Central hub in EMT induction?

Johanna Ivaska
Pages 51 - 53
http://dx.doi.org/10.4161/sgtp.2.1.15114
Abstract | PDF

Epithelial- to-mesenchymal transition (EMT) is a critical event in the induction of cell motility and increased survival both under physiological situations like wound healing and during development as well as in malignant cells undergoing invasion and metastasis. Vimentin is an intermediate filament protein which is characteristically upregulated in cells undergoing EMT. For decades vimentin has been considered as a marker for EMT but its functional contribution to the process has remained unclear. Our data demonstrate that vimentin contributes to EMT via upregulating the gene expression of several EMT-linked genes. Especially, we find that vimentin regulates EMT associated induced migration via upregulation of the expression of receptor tyrosine kinase Axl. In addition to our data, several other exciting recent studies support the notion that vimentin in fact functions as a positive regulator of EMT and upregulation of vimentin appears to be a prerequisite for EMT induction.

Open Access Article

Signaling of the direction-sensing FAK/RACK1/PDE4D5 complex to the small GTPase Rap1

Bryan Serrels, Emma Sandilands and Margaret C. Frame
Pages 54 - 61
http://dx.doi.org/10.4161/sgtp.2.1.15137
Abstract | PDF

We recently reported that a complex between focal adhesion kianse (FAK) and the molecular scaffold RACK1 controlled nascent integrin adhesion formation and cell polarization, via peripheral recruitment of the cAMP-degrading PDE4D5 isoform. Here we review and extend these studies by demonstrating that the FAK/RACK1/PDE4D5 ‘direction-sensing’ complex likely functions by signaling, via the guanine nucleotide exchange factor EPAC, to its small GTPase target Rap1. Specifically, activating EPAC suppresses polarization of squamous cancer cells, while, in contrast, modulating PKA, the other major cAMP effector, has no effect. Moreover, FAK-deficient malignant keratinocytes re-expressing a FAK mutant that cannot bind to RACK1, namely FAK-E139A,D140A, display elevated Rap1 that is linked to impaired polarization. Thus, it is likely that the FAK/RACK1/PDE4D5 complex signals to keep Rap1 low at appropriate times and in a spatially-regulated manner as cells first sense their environment and make decisions about nascent adhesion stabilization and polarization. RACK1 is abundantly expressed in both normal and malignant keratinocytes, while FAK and PDE4D5 are both elevated in the cancer cells, suggesting that the FAK/RACK1/PDE4D5/Rap1 signaling axis may contribute to FAK’s well documented role in tumor progression.