Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.
Adaptor Proteins, Signal Transducing
/ metabolism
Biomolecular Condensates
/ metabolism
Cytoplasmic Granules
/ metabolism
Enzyme Activation
GRB2 Adaptor Protein
/ genetics
HEK293 Cells
Humans
Neoplasms
/ metabolism
Oncogene Proteins, Fusion
/ metabolism
SOS1 Protein
/ metabolism
Signal Transduction
ras Proteins
/ metabolism
ALK
MAPK
RAS
RET
anaplastic lymphoma kinase
biomolecular condensate
gene fusion
kinase
protein granule
receptor tyrosine kinase
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
13 05 2021
13 05 2021
Historique:
received:
07
04
2020
revised:
14
12
2020
accepted:
15
03
2021
pubmed:
14
4
2021
medline:
22
12
2021
entrez:
13
4
2021
Statut:
ppublish
Résumé
Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.
Identifiants
pubmed: 33848463
pii: S0092-8674(21)00362-7
doi: 10.1016/j.cell.2021.03.031
pmc: PMC8127962
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
EML4-ALK fusion protein, human
0
GAB1 protein, human
0
GRB2 Adaptor Protein
0
GRB2 protein, human
0
Oncogene Proteins, Fusion
0
SOS1 Protein
0
SOS1 protein, human
0
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2649-2664.e18Subventions
Organisme : NCI NIH HHS
ID : U01 CA217882
Pays : United States
Organisme : NIGMS NIH HHS
ID : R00 GM126136
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA210444
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224081
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM131641
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213775
Pays : United States
Organisme : NIGMS NIH HHS
ID : R21 GM129652
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM124334
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA128583
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204302
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007618
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA126792
Pays : United States
Organisme : NIGMS NIH HHS
ID : K99 GM126136
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211052
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA231300
Pays : United States
Organisme : NCI NIH HHS
ID : U19 CA179512
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169338
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declarations of interest T.G.B. is an advisor to Array Biopharma/Pfizer, Revolution Medicines, Relay Therapeutics, Rain Therapeutics, Novartis, AstraZeneca, Takeda, Springworks, and Jazz Pharmaceuticals and receives research funding from Novartis, Revolution Medicines, and Strategia.
Références
Cell. 2015 Aug 27;162(5):1066-77
pubmed: 26317470
Mol Cell Biol. 1993 Dec;13(12):7587-95
pubmed: 8246975
Mol Biol Cell. 2008 Oct;19(10):4154-66
pubmed: 18653466
Proc Natl Acad Sci U S A. 1990 Apr;87(8):3042-6
pubmed: 2183224
Cell Signal. 2015 Oct;27(10):1963-76
pubmed: 26163824
Cell. 2017 Sep 21;171(1):163-178.e19
pubmed: 28844694
Nat Rev Cancer. 2017 Oct 25;17(11):637-658
pubmed: 29068003
Cell. 2019 Jan 24;176(3):419-434
pubmed: 30682370
Nat Med. 2015 Sep;21(9):1038-47
pubmed: 26301689
Curr Protoc Mol Biol. 2010 Oct;Chapter 14:Unit14.20
pubmed: 20890901
Nat Methods. 2016 Jul;13(7):557-62
pubmed: 27240257
Cancers (Basel). 2017 Sep 05;9(9):
pubmed: 28872581
Nat Commun. 2017 Aug 29;8(1):370
pubmed: 28851864
Science. 2001 Dec 7;294(5549):2179-81
pubmed: 11679632
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15500-5
pubmed: 16223883
EMBO Rep. 2012 Aug;13(8):733-40
pubmed: 22732841
Trends Mol Med. 2017 Jan;23(1):59-79
pubmed: 27988109
Cell. 2016 Jan 28;164(3):487-98
pubmed: 26777405
Science. 2016 Apr 29;352(6285):595-9
pubmed: 27056844
Cell. 2010 Jun 25;141(7):1117-34
pubmed: 20602996
Nat Rev Mol Cell Biol. 2017 May;18(5):285-298
pubmed: 28225081
Mol Cancer Res. 2018 Nov;16(11):1724-1736
pubmed: 30002191
Traffic. 2012 Aug;13(8):1106-12
pubmed: 22531034
J Cell Mol Med. 2012 Feb;16(2):237-48
pubmed: 21854543
Science. 2019 Mar 8;363(6431):1098-1103
pubmed: 30846600
J Biol Methods. 2014;1(2):
pubmed: 25606571
J Immunol. 2010 Sep 15;185(6):3536-43
pubmed: 20713885
J Cell Biol. 2005 Jul 18;170(2):261-72
pubmed: 16027222
Cancer Discov. 2018 Jul;8(7):797-799
pubmed: 29967074
Clin Cancer Res. 2017 Apr 15;23(8):1988-1997
pubmed: 27683183
Cell. 1992 Aug 7;70(3):431-42
pubmed: 1322798
Science. 2017 Sep 22;357(6357):
pubmed: 28935776
J Cell Biol. 2003 Jan 20;160(2):165-70
pubmed: 12527752
Cell. 2015 Sep 24;163(1):123-33
pubmed: 26406374
J Cell Biol. 2016 Aug 15;214(4):445-58
pubmed: 27502489
Cell. 2017 Jun 1;169(6):1066-1077.e10
pubmed: 28575670
EMBO J. 1994 Sep 1;13(17):4011-21
pubmed: 7521298
Clin Cancer Res. 2015 Apr 15;21(8):1819-27
pubmed: 25878363
Biochem J. 2015 May 1;467(3):529-36
pubmed: 25740311
Cell Rep. 2019 Dec 17;29(12):4053-4068.e6
pubmed: 31851933
Nature. 2007 Aug 2;448(7153):561-6
pubmed: 17625570
Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1533-1542
pubmed: 31871156
Curr Biol. 1995 Jun 1;5(6):635-42
pubmed: 7552174
Nature. 1993 May 6;363(6424):83-5
pubmed: 8479540
Nature. 1984 Aug 16-22;310(5978):583-6
pubmed: 6087162
Mol Cancer. 2018 Feb 19;17(1):58
pubmed: 29455648
N Engl J Med. 2005 Jul 14;353(2):133-44
pubmed: 16014883
EMBO J. 1996 Jun 17;15(12):3016-27
pubmed: 8670803
Cell. 2018 Apr 5;173(2):321-337.e10
pubmed: 29625050
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
EMBO J. 1994 Mar 1;13(5):1073-83
pubmed: 8131741
Thyroid. 2019 Nov;29(11):1704-1707
pubmed: 31650892
Nature. 1993 May 6;363(6424):85-8
pubmed: 8479541
Mol Cell. 2018 Jan 18;69(2):334-346.e4
pubmed: 29307513
Methods Mol Biol. 2014;1120:285-305
pubmed: 24470033
Proc Natl Acad Sci U S A. 1986 Feb;83(4):952-6
pubmed: 3513168
Elife. 2015 Aug 04;4:e06807
pubmed: 26238190
Mol Cell. 2017 Feb 2;65(3):416-431.e6
pubmed: 28157504