Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion

Sergi Marco, Matthew Neilson, Madeleine Moore, Arantxa Perez-Garcia, Holly Hall, Louise Mitchell, Sergio Lilla, Giovani R. Blanco, Ann Hedley, Sara Zanivan and Jim C. Norman ()
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Sergi Marco: CRUK Beatson Institute
Matthew Neilson: CRUK Beatson Institute
Madeleine Moore: CRUK Beatson Institute
Arantxa Perez-Garcia: University of Glasgow
Holly Hall: CRUK Beatson Institute
Louise Mitchell: CRUK Beatson Institute
Sergio Lilla: CRUK Beatson Institute
Giovani R. Blanco: CRUK Beatson Institute
Ann Hedley: CRUK Beatson Institute
Sara Zanivan: CRUK Beatson Institute
Jim C. Norman: CRUK Beatson Institute

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26839-y

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