Ras-Specific GTPase-Activating Proteins—Structures, Mechanisms, and Interactions

Scheffzek, Klaus; Shivalingaiah, Giridhar

doi:10.1101/cshperspect.a031500

Cited by 49 publications

(41 citation statements)

References 214 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the behavior analysis of forebrain-specific Cre-mediated Egr2 deletion mice showed improved learning and memory in specific learning and memory tasks (Poirier et al, 2007). In the same line, we also found that BDNF increased the transcription of Dusp1and Nf1; the products of these genes-a phosphatase and a Ras-GAP, respectively-are known to downregulate Erk1/2 signaling (Lawan et al, 2013;Scheffzek and Shivalingaiah, 2019). However, one of the role associated with Arc in neurons is the endocytosis of AMPA receptors that is required for synaptic depression (Barylko et al, 2018).…”

Section: Discussionsupporting

confidence: 52%

The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons

González

Lazo

Bronfman

2019

Preprint

View full text Add to dashboard Cite

Brain-derived neurotrophic factor (BDNF) is a key regulator of the morphology and connectivity of central neurons. We have previously shown that BDNF/TrkB signaling regulates the activity and mobility of the GTPases Rab5 and Rab11, which in turn determine the post-endocytic sorting of signaling TrkB receptors. Moreover, altered Rab5 or Rab11 activity inhibits BDNF-induced dendritic branching. Whether Rab5 or Rab11 activity is important for local events only, or also for regulating nuclear signaling and gene expression, is unknown. Here, we investigated whether BDNF-induced signaling cascades were altered when early and recycling endosomes were disrupted by the expression of dominant negative mutants of Rab5 and Rab11. The activities of both Rab5 and Rab11 were required for sustained activity of Erk1/2 and nuclear CREB phosphorylation and for increased transcription of BDNF-dependent genes containing CRE-binding sites that include activity-regulated genes such as Arc, Dusp1, c-fos and Egr1 and growth and survival genes such as Atf3 and Nf1. Based on our results, we propose that the early and recycling endosomes provide a platform for the integration of neurotrophic signaling from the plasma membrane to the nucleus in neurons and that this mechanism likely regulates neuronal plasticity and neuronal survival. Significance StatementBDNF is a soluble neurotrophic factor that regulates plastic changes in the brain, including dendritic growth, by binding to its plasma membrane receptor TrkB. BDNF/TrkB activates signaling cascades leading to activation of CREB, a key transcription factor regulating circuit development and learning and memory. Our results uncover the cellular mechanisms that central neurons use to integrate the signaling of plasma membrane receptors with nuclear transcriptional responses. We found that the endosomal pathway is required for the signaling cascade initiated by BDNF and its receptors in the plasma membranes to modulate BDNF-dependent gene expression and neuronal dendritic growth mediated by the CREB transcription factor in the nucleus.

show abstract

Section: Discussionsupporting

confidence: 52%

The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons

González

Lazo

Bronfman

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…A patient mutation substitution of this arginine to a proline residue resulted in an 8000-fold decrease in Ras-GAP activity [44,46].…”

Section: The Gap-related Domain (Grd)mentioning

confidence: 99%

“…Two ligands are involved in this model. Interaction with ligand A induces conformational changes in the β-protrusion of the PH domain, which then releases the lid-helix of the Sec domain and opens the lipid-binding cage, thereby allowing binding of the second ligand B (glycerophospholipids) ( Figure 7) [46,50]. It is possible that Sec ligand B may be a protein and not only a lipid.…”

Section: The Secph Domainmentioning

confidence: 99%

Neurofibromin Structure, Functions and Regulation

Bergoug

Doudeau

Godin

et al. 2020

Cells

106

View full text Add to dashboard Cite

Neurofibromin is a large and multifunctional protein encoded by the tumor suppressor gene NF1, mutations of which cause the tumor predisposition syndrome neurofibromatosis type 1 (NF1). Over the last three decades, studies of neurofibromin structure, interacting partners, and functions have shown that it is involved in several cell signaling pathways, including the Ras/MAPK, Akt/mTOR, ROCK/LIMK/cofilin, and cAMP/PKA pathways, and regulates many fundamental cellular processes, such as proliferation and migration, cytoskeletal dynamics, neurite outgrowth, dendritic-spine density, and dopamine levels. The crystallographic structure has been resolved for two of its functional domains, GRD (GAP-related (GTPase-activating protein) domain) and SecPH, and its post-translational modifications studied, showing it to be localized to several cell compartments. These findings have been of particular interest in the identification of many therapeutic targets and in the proposal of various therapeutic strategies to treat the symptoms of NF1. In this review, we provide an overview of the literature on neurofibromin structure, function, interactions, and regulation and highlight the relationships between them.

show abstract

“…Consequently, loss of function of RasGAPs leads to aberrant Ras activation and increases downstream oncogenic signaling. Currently, there are 14 recognized RasGAP genes in the human genome; they all contain a GAP domain, but share limited similarity outside this region [ 11 , 12 ]. A set of additional modules is common in RasGAPs, such as Ca 2+ -binding domains (C2) and phosphatidylinositol lipid-binding motifs (pleckstrin homology (PH)).…”

Section: The Brakes: Gaps As Negative Regulators Of Ras Activitymentioning

confidence: 99%

“…A set of additional modules is common in RasGAPs, such as Ca 2+ -binding domains (C2) and phosphatidylinositol lipid-binding motifs (pleckstrin homology (PH)). The protein architecture and specific domains define six RasGAP subfamilies of shared structure and function ( Figure 1 ; for a detailed description see [ 11 , 12 ]).…”

Section: The Brakes: Gaps As Negative Regulators Of Ras Activitymentioning

confidence: 99%

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

Bellazzo

Collavin

2020

Cancers

View full text Add to dashboard Cite

The Ras pathway is frequently deregulated in cancer, actively contributing to tumor development and progression. Oncogenic activation of the Ras pathway is commonly due to point mutation of one of the three Ras genes, which occurs in almost one third of human cancers. In the absence of Ras mutation, the pathway is frequently activated by alternative means, including the loss of function of Ras inhibitors. Among Ras inhibitors, the GTPase-Activating Proteins (RasGAPs) are major players, given their ability to modulate multiple cancer-related pathways. In fact, most RasGAPs also have a multi-domain structure that allows them to act as scaffold or adaptor proteins, affecting additional oncogenic cascades. In cancer cells, various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms. We also consider extracellular inputs that can affect RasGAP levels and functions, implicating that specific conditions in the tumor microenvironment can foster or counteract Ras signaling through negative or positive modulation of RasGAPs. A better understanding of these conditions might have relevant clinical repercussions, since treatments to restore or enhance the function of RasGAPs in cancer would help circumvent the intrinsic difficulty of directly targeting the Ras protein.

show abstract

Ras-Specific GTPase-Activating Proteins—Structures, Mechanisms, and Interactions

Cited by 49 publications

References 214 publications

The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons

The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in neurons

Neurofibromin Structure, Functions and Regulation

Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

Contact Info

Product

Resources

About