KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

Rabara, Dana; Tran, Timothy H.; Dharmaiah, Srisathiyanarayanan; Stephens, Robert M.; McCormick, Frank; Simanshu, Dhirendra K.; Holderfield, Matthew

doi:10.1073/pnas.1908353116

Cited by 100 publications

(107 citation statements)

References 40 publications

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“…More recently, the 3D structure of a complex between K-Ras (GMPPNP-bound) and a fragment of the neurofibromin-GRD (GAP255: residues 1209 to 1463), corresponding to the minimum catalytic region (the C-and N-terminal regions forming the extra domain were excluded), was resolved [47] ( Figure 5), confirming the insights given by the model. This was the first structure of a Rasneurofibromin GRD complex and of a Ras-Ras GAP complex in the ground-state conformation.…”

Section: The Gap-related Domain (Grd)supporting

confidence: 61%

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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Section: The Gap-related Domain (Grd)supporting

confidence: 61%

Neurofibromin Structure, Functions and Regulation

Bergoug

Doudeau

Godin

et al. 2020

Cells

106

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“…RAS proteins have two mutational hotspots, 12-13 and 61. Most mutations changing G12 or G13, likely to intercept GAP's Arg finger loop accession to the RAS GTPase site and prevent it from promoting hydrolysis [246][247][248]. As a consequence, G12 and G13 mutants trap RAS in a constitutively active state.…”

Section: Ras Mutationsmentioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

402

303

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The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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“…The GRD has a central portion called the minimal catalytic domain (GAPc) and an extra domain (GAPex) formed by residues that flank the GAPc. Although the apo structure of the NF1(GRD) was solved more than 2 decades ago ( Scheffzek et al, 1998 ), our recent structural work on GMPPNP-bound KRAS in complex with the GAPc of NF1(GRD) provided structural insights into NF1-mediated GTPase activity ( Rabara et al, 2019 ). In that study, we showed that, unlike G12 and Q61 mutants, G13 mutants of KRAS are frequently co-mutated with NF1 and that NF1 hydrolyzes GTP directly in complex with KRAS-G13D.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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SUMMARY Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SPRED1 and NF1 loss-of-function mutations occur across multiple cancer types and developmental diseases. Analysis of the neurofibromin-SPRED1 interface provides a rationale for mutations observed in Legius syndrome and suggests why SPRED1 can bind to neurofibromin but no other RasGAPs. We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.

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KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

Cited by 100 publications

References 40 publications

Neurofibromin Structure, Functions and Regulation

Neurofibromin Structure, Functions and Regulation

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

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

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