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

Marco, S. et al. (2021) Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion. Nature Communications, 12, 6829. (doi: 10.1038/s41467-021-26839-y) (PMID:34819513) (PMCID:PMC8613289)

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.

• Item Type: Articles
• Additional Information: This work was funded by Cancer Research UK (Core grants: A17196 and A31287, JCN grant: A18277 and SZ grant: A29800).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lilla, Dr Sergio and Norman, Professor James and Zanivan, Professor Sara and Neilson, Dr Matthew and Mitchell, Mrs Louise
• Authors: Marco, S., Neilson, M., Moore, M., Perez-Garcia, A., Hall, H., Mitchell, L., Lilla, S., Blanco, G. R., Hedley, A., Zanivan, S., and Norman, J. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group UK
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2021
• First Published: First published in Nature Communications 12(1):6829
• Publisher Policy: Reproduced under a Creative Commons Licence