Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.
Adaptor Proteins, Signal Transducing
/ chemistry
Amino Acid Sequence
Cafe-au-Lait Spots
/ genetics
Catalytic Domain
DNA Mutational Analysis
Epidermal Growth Factor
/ pharmacology
ErbB Receptors
/ metabolism
Guanosine Triphosphate
/ metabolism
HEK293 Cells
Humans
K562 Cells
Neurofibromatosis 1
/ genetics
Neurofibromin 1
/ chemistry
Oncogenes
Phosphorylation
Point Mutation
/ genetics
Protein Binding
Protein Domains
Protein Interaction Maps
Proto-Oncogene Proteins p21(ras)
/ chemistry
Signal Transduction
Legius syndrome
RAS-RAF-ERK pathway
RASopathy
RasGAP
neurofibromatosis type 1
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
21 07 2020
21 07 2020
Historique:
received:
20
12
2019
revised:
25
05
2020
accepted:
24
06
2020
entrez:
23
7
2020
pubmed:
23
7
2020
medline:
29
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32697994
pii: S2211-1247(20)30890-1
doi: 10.1016/j.celrep.2020.107909
pmc: PMC7437355
mid: NIHMS1613940
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
KRAS protein, human
0
Neurofibromin 1
0
SPRED1 protein, human
0
Epidermal Growth Factor
62229-50-9
Guanosine Triphosphate
86-01-1
ErbB Receptors
EC 2.7.10.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
107909Subventions
Organisme : NCI NIH HHS
ID : R35 CA197709
Pays : United States
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR029205
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200800001E
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests F.M. is a consultant for the following companies: Aduro Biotech, Amgen, Daiichi, Ideaya Biosciences, Kura Oncology, Leidos Biomedical Research, PellePharm, Pfizer, PMV Pharma, Portola Pharmaceuticals, and Quanta Therapeutics; has received research grants from Daiichi; is a recipient of funded research from Gilead Sciences; is a consultant and cofounder for the following companies (with ownership interest, including stock options): BridgeBio Pharma, DNAtrix, Olema Pharmaceuticals, and Quartz.
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