Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

Carabias, Arturo; Gómez-Hernández, María Teresa; Cima, Sergio de; Rodríguez-Blázquez, Antonio; Morán-Vaquero, Alba; González-Sáenz, Patricia; Guerrero, Carmen; Pereda, José M. de

doi:10.1126/scisignal.abb7075

Cited by 13 publications

(56 citation statements)

References 88 publications

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“…C3G is involved in signaling to gene expression and cytoskeletal reorganization, and therefore regulates diverse cellular responses like proliferation, adhesion, migration, survival, and differentiation. Mutations and deregulation of C3G expression are associated with a variety of disorders [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells

Vishnu

Muralikrishna

Nayak

et al. 2021

Stem Cell Rev and Rep

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SummaryC3G (RAPGEF1), engaged in multiple signaling pathways, is essential for the early development of the mouse. In this study, we have examined its role in mouse embryonic stem cell self-renewal and differentiation. C3G null cells generated by CRISPR mediated knock-in of a targeting vector exhibited enhanced clonogenicity and long-term self-renewal. They did not differentiate in response to LIF withdrawal when compared to the wild type ES cells and were defective for lineage commitment upon teratoma formation in vivo. Gene expression analysis of C3G KO cells showed misregulated expression of a large number of genes compared with WT cells. They express higher levels of self-renewal factors like KLF4 and ESRRB and show high STAT3 activity, and very low ERK activity compared to WT cells. Reintroduction of C3G expression in a KO line partially reverted expression of ESRRB, and KLF4, and ERK activity similar to that seen in WT cells. The expression of self-renewal factors was persistent for a longer time, and induction of lineage-specific markers was not seen when C3G KO cells were induced to form embryoid bodies. C3G KO cells showed poor adhesion and significantly reduced levels of pFAK, pPaxillin, and Integrin-β1, in addition to downregulation of the cluster of genes involved in cell adhesion, compared to WT cells. Our results show that C3G is essential for the regulation of STAT3, ERK, and adhesion signaling, to maintain pluripotency of mouse embryonic stem cells and enable their lineage commitment for differentiation. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells

Vishnu

Muralikrishna

Nayak

et al. 2021

Stem Cell Rev and Rep

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“…Notably, not all structural mechanisms commonly adopted by driver mutations can be directly targeted by drugs. A case in point is relieving the autoinhibition, another frequent mutation strategy 13,85–100 . The significance of a molecular view of MOA as compared with a traditional phenomenological outlook is evidenced from refocusing the therapeutics from tissue‐ or cancer type‐based, to cancer genomics and accurate protein structural data.…”

Section: The Traditional Moa Classificationmentioning

confidence: 99%

Mechanism of activation and the rewired network: New drug design concepts

Nussinov

Zhang

Maloney

et al. 2021

Medicinal Research Reviews

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Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same‐allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure‐based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor‐specific network, ushering innovative considerations in precision medicine.

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“…Moreover, C3G downregulation enhances the STI-571 (imatinib mesylate) pro-apoptotic effect in CML cells [ 61 ]. In non-Hodgkin’s lymphoma patients, two missense mutations have been found in the C3G N-terminal region that causes Rap1 hyperactivation [ 62 ], which might lead to lymphoma progression ( Table 1 ).…”

Section: Actions Of C3g In Gbm: What Is Different Compared To Other Tumours?mentioning

confidence: 99%

“…It is important to highlight the relevance of a fine tune regulation of C3G levels across tissues [ 25 ] and how their dysregulation is associated with different tumour types, as observed in multiple studies: non-small lung carcinoma [ 53 ], CML [ 60 ], neuroblastoma and pheochromocytoma [ 46 ], breast carcinoma [ 58 ], ovarian cancer [ 59 ], CRC [ 55 ], HCC [ 56 , 57 ], non-Hodgkins lymphoma [ 62 ], and GBM [ 63 ].…”

Section: C3g In Clinics: Present and Future Perspectivesmentioning

confidence: 99%

C3G Protein, a New Player in Glioblastoma

Manzano

Gutiérrez-Uzquiza

Bragado

et al. 2021

IJMS

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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.

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Mechanisms of autoregulation of C3G, activator of the GTPase Rap1, and its catalytic deregulation in lymphomas

Cited by 13 publications

References 88 publications

C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells

C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells

Mechanism of activation and the rewired network: New drug design concepts

C3G Protein, a New Player in Glioblastoma

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