Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state.
FGFR2
Liquid-liquid phase separation (LLPS)
Plcγ1
Receptor tyrosine kinases (RTKs)
Shp2
kinase activity
phosphatase activity
phospholipase activity
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 03 2022
17 03 2022
Historique:
received:
23
10
2019
revised:
02
11
2021
accepted:
01
02
2022
pubmed:
2
3
2022
medline:
5
4
2022
entrez:
1
3
2022
Statut:
ppublish
Résumé
The recruitment of signaling proteins into activated receptor tyrosine kinases (RTKs) to produce rapid, high-fidelity downstream response is exposed to the ambiguity of random diffusion to the target site. Liquid-liquid phase separation (LLPS) overcomes this by providing elevated, localized concentrations of the required proteins while impeding competitor ligands. Here, we show a subset of phosphorylation-dependent RTK-mediated LLPS states. We then investigate the formation of phase-separated droplets comprising a ternary complex including the RTK, (FGFR2); the phosphatase, SHP2; and the phospholipase, PLCγ1, which assembles in response to receptor phosphorylation. SHP2 and activated PLCγ1 interact through their tandem SH2 domains via a previously undescribed interface. The complex of FGFR2 and SHP2 combines kinase and phosphatase activities to control the phosphorylation state of the assembly while providing a scaffold for active PLCγ1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention.
Identifiants
pubmed: 35231400
pii: S1097-2765(22)00110-1
doi: 10.1016/j.molcel.2022.02.005
pmc: PMC8937303
pii:
doi:
Substances chimiques
Tyrosine
42HK56048U
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1089-1106.e12Subventions
Organisme : Medical Research Council
ID : MR/K015613/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C57233/A22356
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S015787/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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