Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion.
Actins
/ metabolism
Active Transport, Cell Nucleus
/ genetics
Animals
Cell Line, Tumor
Cell Nucleus
/ metabolism
Cytoplasm
/ metabolism
Endosomes
/ metabolism
Gene Expression Regulation, Neoplastic
Hepatocyte Growth Factor
/ metabolism
Humans
Mice
Mice, Knockout
Neoplasm Invasiveness
/ genetics
Neoplasms
/ pathology
Receptor Protein-Tyrosine Kinases
/ genetics
Ternary Complex Factors
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 11 2021
24 11 2021
Historique:
received:
29
07
2020
accepted:
21
10
2021
entrez:
25
11
2021
pubmed:
26
11
2021
medline:
24
12
2021
Statut:
epublish
Résumé
Signals are relayed from receptor tyrosine kinases (RTKs) at the cell surface to effector systems in the cytoplasm and nucleus, and coordination of this process is important for the execution of migratory phenotypes, such as cell scattering and invasion. The endosomal system influences how RTK signalling is coded, but the ways in which it transmits these signals to the nucleus to influence gene expression are not yet clear. Here we show that hepatocyte growth factor, an activator of MET (an RTK), promotes Rab17- and clathrin-dependent endocytosis of EphA2, another RTK, followed by centripetal transport of EphA2-positive endosomes. EphA2 then mediates physical capture of endosomes on the outer surface of the nucleus; a process involving interaction between the nuclear import machinery and a nuclear localisation sequence in EphA2's cytodomain. Nuclear capture of EphA2 promotes RhoG-dependent phosphorylation of the actin-binding protein, cofilin to oppose nuclear import of G-actin. The resulting depletion of nuclear G-actin drives transcription of Myocardin-related transcription factor (MRTF)/serum-response factor (SRF)-target genes to implement cell scattering and the invasive behaviour of cancer cells.
Identifiants
pubmed: 34819513
doi: 10.1038/s41467-021-26839-y
pii: 10.1038/s41467-021-26839-y
pmc: PMC8613289
doi:
Substances chimiques
Actins
0
Ternary Complex Factors
0
Hepatocyte Growth Factor
67256-21-7
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6829Subventions
Organisme : Cancer Research UK
ID : A18277
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29800
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A31287
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P01058X/1
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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