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

  1. Author:
    Yan,Wupeng
    Markegard, Evan
    Dharmaiah, Srisathiyanarayanan
    Urisman, Anatoly
    Drew, Matthew
    Esposito,Dom
    Scheffzek, Klaus
    Nissley,Dwight
    McCormick, Frank
    Simanshu,Dhirendra

  2. Author Address

    NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA., Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria., NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: frank.mccormick@ucsf.edu., NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA. Electronic address: dhirendra.simanshu@fnlcr.nih.gov.,
    1. Year: 2020
    2. Date: Jul 21
  2. Journal: Cell reports
    1. 32
    2. 3
    3. Pages: 107909
  4. Type of Article: Article
  5. Article Number: 107909
  6. ISSN: 2211-1247
  1. Abstract:

    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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2020.107909
  3. PMID: 32697994
  4. View record in Web of Science®
  5. WOS: 000552075500003
  6. PII : S2211-1247(20)30890-1

Library Notes

  1. Fiscal Year: FY2019-2020
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