Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR

Yan, Wang; Markegard, Evan; Dharmaiah, Srisathiyanarayanan; Tlsty, Thea D.; Drew, Matthew; Esposito, Dominic; Scheffzek, Klaus; Nissley, Dwight V.; McCormick, Frank; Simanshu, Dhirendra K.

doi:10.1016/j.celrep.2020.107909

Cited by 53 publications

(57 citation statements)

References 75 publications

(117 reference statements)

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“…Hence, effector activation and Ras inactivation appear to be tightly coupled. Furthermore, given the involvement of multiple protein interactions, several context-dependent regulation mechanisms are possible during these steps [34]. It can be concluded that, at least in this particular case, the plasma membrane is the major site of Ras activity.…”

Section: Ras In the Plasma Membranementioning

confidence: 99%

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Abankwa

Gorfe

2020

Biomolecules

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Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanoclusters. We discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization while the whole Ras/RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

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Section: Ras In the Plasma Membranementioning

confidence: 99%

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Abankwa

Gorfe

2020

Biomolecules

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“…Hence, effector activation and Ras inactivation appear to be tightly coupled. Furthermore, given the involvement of multiple protein interactions, several context-dependent regulation mechanisms are possible during these steps [33]. It can be concluded that, at least in this particular case, the plasma membrane is the major site of Ras activity.…”

Section: Ras In the Plasma Membranementioning

confidence: 99%

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Abankwa¹,

Gorfe²

2020

Preprint

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Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we will review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanocluster. We will discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We will then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we will show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/ neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization, while the whole Ras/ RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including, whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster.

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“…Neurofibromin translocation to the cell membrane enables its localization in proximity to Ras for possibly more efficient downregulation of Ras by its Ras-GAP activity. Recently, Yan et al (2020) [77] resolved the structure of a trimeric complex between the neurofibromin GRD, the Spred1-EVH1 domain, and K-Ras, allowing a precise analysis of the neurofibromin/Spred1 interface. This provided a rationale for the mutations observed in Legius syndrome and revealed mechanistic insights concerning K-Ras regulation.…”

Section: Plasma Membrane Localizationmentioning

confidence: 99%

Neurofibromin Structure, Functions and Regulation

Bergoug

Doudeau

Godin

et al. 2020

Cells

106

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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.

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Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR

Cited by 53 publications

References 75 publications

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

Neurofibromin Structure, Functions and Regulation

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