scholarly journals C3G Protein, a New Player in Glioblastoma

2021 ◽  
Vol 22 (18) ◽  
pp. 10018
Author(s):  
Sara Manzano ◽  
Alvaro Gutierrez-Uzquiza ◽  
Paloma Bragado ◽  
Angel M Cuesta ◽  
Carmen Guerrero ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Protein A ◽  
Patient Treatment ◽  
Migration And Invasion ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Mesenchymal Phenotype ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Personalised Treatment

C3G (RAPGEF1) is a guanine nucleotide exchange factor (GEF) for GTPases from the Ras superfamily, mainly Rap1, although it also acts through GEF-independent mechanisms. C3G regulates several cellular functions. It is expressed at relatively high levels in specific brain areas, playing important roles during embryonic development. Recent studies have uncovered different roles for C3G in cancer that are likely to depend on cell context, tumour type, and stage. However, its role in brain tumours remained unknown until very recently. We found that C3G expression is downregulated in GBM, which promotes the acquisition of a more mesenchymal phenotype, enhancing migration and invasion, but not proliferation. ERKs hyperactivation, likely induced by FGFR1, is responsible for this pro-invasive effect detected in C3G silenced cells. Other RTKs (Receptor Tyrosine Kinases) are also dysregulated and could also contribute to C3G effects. However, it remains undetermined whether Rap1 is a mediator of C3G actions in GBM. Various Rap1 isoforms can promote proliferation and invasion in GBM cells, while C3G inhibits migration/invasion. Therefore, other RapGEFs could play a major role regulating Rap1 activity in these tumours. Based on the information available, C3G could represent a new biomarker for GBM diagnosis, prognosis, and personalised treatment of patients in combination with other GBM molecular markers. The quantification of C3G levels in circulating tumour cells (CTCs) in the cerebrospinal liquid and/or circulating fluids might be a useful tool to improve GBM patient treatment and survival.

scholarly journals Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1

2003 ◽  
Vol 160 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Metello Innocenti ◽  
Emanuela Frittoli ◽  
Isabella Ponzanelli ◽  
John R. Falck ◽  
Saskia M. Brachmann ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Physical Interaction ◽  
Nucleotide Exchange ◽  
Downstream Target ◽  
Signaling Complex ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Phosphoinositide 3 Kinase

Class I phosphoinositide 3-kinases (PI3Ks) are implicated in many cellular responses controlled by receptor tyrosine kinases (RTKs), including actin cytoskeletal remodeling. Within this pathway, Rac is a key downstream target/effector of PI3K. However, how the signal is routed from PI3K to Rac is unclear. One possible candidate for this function is the Rac-activating complex Eps8–Abi1–Sos-1, which possesses Rac-specific guanine nucleotide exchange factor (GEF) activity. Here, we show that Abi1 (also known as E3b1) recruits PI3K, via p85, into a multimolecular signaling complex that includes Eps8 and Sos-1. The recruitment of p85 to the Eps8–Abi1–Sos-1 complex and phosphatidylinositol 3, 4, 5 phosphate (PIP3), the catalytic product of PI3K, concur to unmask its Rac-GEF activity in vitro. Moreover, they are indispensable for the activation of Rac and Rac-dependent actin remodeling in vivo. On growth factor stimulation, endogenous p85 and Abi1 consistently colocalize into membrane ruffles, and cells lacking p85 fail to support Abi1-dependent Rac activation. Our results define a mechanism whereby propagation of signals, originating from RTKs or Ras and leading to actin reorganization, is controlled by direct physical interaction between PI3K and a Rac-specific GEF complex.

scholarly journals ARL3 and ARL13B GTPases participate in distinct steps of INPP5E targeting to the ciliary membrane

Biology Open ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Sayaka Fujisawa ◽  
Hantian Qiu ◽  
Shohei Nozaki ◽  
Shuhei Chiba ◽  
Yohei Katoh ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factor ◽  
Membrane Localization ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Ciliary Membrane ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Direct Binding ◽  
Ciliary Localization

ABSTRACT INPP5E, a phosphoinositide 5-phosphatase, localizes on the ciliary membrane via its C-terminal prenyl moiety, and maintains the distinct ciliary phosphoinositide composition. The ARL3 GTPase contributes to the ciliary membrane localization of INPP5E by stimulating the release of PDE6D bound to prenylated INPP5E. Another GTPase, ARL13B, which is localized on the ciliary membrane, contributes to the ciliary membrane retention of INPP5E by directly binding to its ciliary targeting sequence. However, as ARL13B was shown to act as a guanine nucleotide exchange factor (GEF) for ARL3, it is also possible that ARL13B indirectly mediates the ciliary INPP5E localization via activating ARL3. We here show that INPP5E is delocalized from cilia in both ARL3-knockout (KO) and ARL13B-KO cells. However, some of the abnormal phenotypes were different between these KO cells, while others were found to be common, indicating the parallel roles of ARL3 and ARL13B, at least concerning some cellular functions. For several variants of ARL13B, their ability to interact with INPP5E, rather than their ability as an ARL3-GEF, was associated with whether they could rescue the ciliary localization of INPP5E in ARL13B-KO cells. These observations together indicate that ARL13B determines the ciliary localization of INPP5E, mainly by its direct binding to INPP5E.

scholarly journals Mechanisms through which Sos-1 coordinates the activation of Ras and Rac

2002 ◽  
Vol 156 (1) ◽  
pp. 125-136 ◽  
Author(s):  
Metello Innocenti ◽  
Pierluigi Tenca ◽  
Emanuela Frittoli ◽  
Mario Faretta ◽  
Arianna Tocchetti ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Adaptor Protein ◽  
Small Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Son Of Sevenless ◽  
Sequential Activation

Signaling from receptor tyrosine kinases (RTKs)* requires the sequential activation of the small GTPases Ras and Rac. Son of sevenless (Sos-1), a bifunctional guanine nucleotide exchange factor (GEF), activates Ras in vivo and displays Rac-GEF activity in vitro, when engaged in a tricomplex with Eps8 and E3b1–Abi-1, a RTK substrate and an adaptor protein, respectively. A mechanistic understanding of how Sos-1 coordinates Ras and Rac activity is, however, still missing. Here, we demonstrate that (a) Sos-1, E3b1, and Eps8 assemble into a tricomplex in vivo under physiological conditions; (b) Grb2 and E3b1 bind through their SH3 domains to the same binding site on Sos-1, thus determining the formation of either a Sos-1–Grb2 (S/G) or a Sos-1–E3b1–Eps8 (S/E/E8) complex, endowed with Ras- and Rac-specific GEF activities, respectively; (c) the Sos-1–Grb2 complex is disrupted upon RTKs activation, whereas the S/E/E8 complex is not; and (d) in keeping with the previous result, the activation of Ras by growth factors is short-lived, whereas the activation of Rac is sustained. Thus, the involvement of Sos-1 at two distinct and differentially regulated steps of the signaling cascade allows for coordinated activation of Ras and Rac and different duration of their signaling within the cell.

Multiple Phosphorylation Sites and Quaternary Organization of Guanine-Nucleotide Exchange Complex of Elongation Factor-1 (EF-1βγδ/ValRS) Control the Various Functions of EF-1α

1998 ◽  
Vol 18 (3) ◽  
pp. 119-127 ◽  
Author(s):  
Odile Minella ◽  
Odile Mulner-Lorillon ◽  
Guillaume Bec ◽  
Patrick Cormier ◽  
Robert Bellé
Keyword(s):  
Structural Model ◽  
Elongation Factor ◽  
Trna Synthetase ◽  
Macromolecular Complex ◽  
Phosphorylation Sites ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

The eukaryotic guanine-nucleotide exchange factor commonly called elongation factor-1βγδ (EF-1βγδ), comprises four different subunits including valyl-tRNA synthetase (EF-1βγδ/ValRS). The factor is multiply-phosphorylated by three different protein kinases, protein kinase C, casein kinase II and cyclin dependent kinase 1 (CDK1). EF-1βγδ/ValRS is organized as a macromolecular complex for which we propose a new structural model. Evidence that EF-1βγδ/ValRS is a sophisticated supramolecular complex containing many phosphorylation sites, makes it a potential regulator of any of the functions of its partner EF-1α, not only involved in protein synthesis elongation, but also in many other cellular functions.

scholarly journals A NUMB–EFA6B–ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

2018 ◽  
Vol 217 (9) ◽  
pp. 3161-3182 ◽  
Author(s):  
Martina Zobel ◽  
Andrea Disanza ◽  
Francesca Senic-Matuglia ◽  
Michel Franco ◽  
Ivan Nicola Colaluca ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Migration And Invasion ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Endocytic Protein ◽  
Membrane Protrusions

The endocytic protein NUMB has been implicated in the control of various polarized cellular processes, including the acquisition of mesenchymal migratory traits through molecular mechanisms that have only been partially defined. Here, we report that NUMB is a negative regulator of a specialized set of understudied, apically restricted, actin-based protrusions, the circular dorsal ruffles (CDRs), induced by either PDGF or HGF stimulation. Through its PTB domain, NUMB binds directly to an N-terminal NPLF motif of the ARF6 guanine nucleotide exchange factor, EFA6B, and promotes its exchange activity in vitro. In cells, a NUMB–EFA6B–ARF6 axis regulates the recycling of the actin regulatory cargo RAC1 and is critical for the formation of CDRs that mark the acquisition of a mesenchymal mode of motility. Consistently, loss of NUMB promotes HGF-induced cell migration and invasion. Thus, NUMB negatively controls membrane protrusions and the acquisition of mesenchymal migratory traits by modulating EFA6B–ARF6 activity.

scholarly journals Ras Is Required for the Cyclic AMP-Dependent Activation of Rap1 via Epac2

2008 ◽  
Vol 28 (23) ◽  
pp. 7109-7125 ◽  
Author(s):  
Chang Liu ◽  
Maho Takahashi ◽  
Yanping Li ◽  
Shuang Song ◽  
Tara J. Dillon ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Sympathetic Neurons ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Bona Fide ◽  
First Time

ABSTRACT Exchange proteins activated by cAMP (cyclic AMP) 2 (Epac2) is a guanine nucleotide exchange factor for Rap1, a small G protein involved in many cellular functions, including cell adhesion, differentiation, and exocytosis. Epac2 interacts with Ras-GTP via a Ras association (RA) domain. Previous studies have suggested that the RA domain was dispensable for Epac2 function. Here we show for the first time that Ras and cAMP regulate Epac2 function in a parallel fashion and the Ras-Epac2 interaction is required for the cAMP-dependent activation of endogenous Rap1 by Epac2. The mechanism for this requirement is not allosteric activation of Epac2 by Ras but the compartmentalization of Epac2 on the Ras-containing membranes. A computational modeling is consistent with this compartmentalization being a function of both the level of Ras activation and the affinity between Ras and Epac2. In PC12 cells, a well-established model for sympathetic neurons, the Epac2 signaling is coupled to activation of mitogen-activated protein kinases and contributes to neurite outgrowth. Taken together, the evidence shows that Epac2 is not only a cAMP sensor but also a bona fide Ras effector. Coincident detection of both cAMP and Ras signals is essential for Epac2 to activate Rap1 in a temporally and spatially controlled manner.

scholarly journals Advances and Insights of APC-Asef Inhibitors for Metastatic Colorectal Cancer Therapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiuyan Yang ◽  
Jie Zhong ◽  
Qiufen Zhang ◽  
Li Feng ◽  
Zhen Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Biology ◽  
Structural Information ◽  
Peptide Inhibitors ◽  
Migration And Invasion ◽  
Nucleotide Exchange ◽  
Protein Protein Interaction ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Two Generations

In Colorectal cancer (CRC), adenomatous polyposis coli (APC) directly interacts with the Rho guanine nucleotide exchange factor 4 (Asef) and releases its GEF activity. Activated Asef promotes the aberrant migration and invasion of CRC cell through a CDC42-mediated pathway. Knockdown of either APC or Asef significantly decreases the migration of CRC cells. Therefore, disrupting the APC-Asef interaction is a promising strategy for the treatment of invasive CRC. With the growth of structural information, APC-Asef inhibitors have been designed, providing hope for CRC therapy. Here, we will review the APC-Asef interaction in cancer biology, the structural complex of APC-Asef, two generations of peptide inhibitors of APC-Asef, and small molecule inhibitors of APC-Asef, focusing on research articles over the past 30 years. We posit that these advances in the discovery of APC-Asef inhibitors establish the protein-protein interaction (PPI) as targetable and provide a framework for other PPI programs.

scholarly journals Rab11 is required for lysosome exocytosis through the interaction with Rab3a, Sec15 and GRAB

2021 ◽  
Author(s):  
Cristina Escrevente ◽  
Liliana Bento-Lopes ◽  
José S. Ramalho ◽  
Duarte C. Barral
Keyword(s):  
Plasma Membrane ◽  
Cell Periphery ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Membrane Repair ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Plasma Membrane Repair ◽  
Molecular Machinery

Lysosomes are dynamic organelles, capable of undergoing exocytosis. This process is crucial for several cellular functions, namely plasma membrane repair. Nevertheless, the molecular machinery involved in this process is poorly understood. Here, we identify Rab11a and Rab11b as regulators of calcium-induced lysosome exocytosis. Interestingly, Rab11-positive vesicles transiently interact with lysosomes at the cell periphery, indicating that this interaction is required for the last steps of lysosome exocytosis. Additionally, we found that the silencing of the exocyst subunit Sec15, a Rab11 effector, impairs lysosome exocytosis, suggesting that Sec15 acts together with Rab11 in the regulation of lysosome exocytosis. Furthermore, we show that Rab11 binds the guanine nucleotide exchange factor for Rab3a (GRAB) and also Rab3a, which we described previously as a regulator of the positioning and exocytosis of lysosomes. Thus, our study identifies new players required for lysosome exocytosis and suggest the existence of a Rab11-Rab3a cascade involved in this process.

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