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The Role of the Adapter Protein Anks1a in the Regulation of Breast Cancer Cell Motility

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Abstract

Epithelial–mesenchymal transition (EMT) is a critical step in tumor progression that leads to the acquisition by cancer cells the capacity for migration using the mesenchymal motility mode regulated by the Rac→WAVE→Arp2/3 signaling pathway. Earlier it was shown that proteins interacting with Rac can regulate mesenchymal migration and thus determine the metastatic potential of the cells. The search for new regulators of cell migration is an important theoretical and practical task. The adaptor protein Anks1a is one of the proteins interacting with Rac, whose expression is altered in many types of tumors. The aim of this study was to find whether Anks1a affects the migration of cancer cells and to identify the mechanism underlying this effect. It was suggested that Anks1a can influence cancer cell migration either as a Rac1 effector or by activating human epidermal growth factor receptor 2 (HER2) exchange. We investigated how upregulation and inhibition of Anks1a expression affected migration of breast cancer cells with different HER2 status. Anks1a was shown to interact with the activated form of Rac1. In the MDA-MB-231 cells (triple negative cancer), which lack HER2, Anks1a accumulated at the active cell edge, which is characterized by enrichment with active Rac1, whereas no such accumulation was observed in the HER2-overexpressing SK-BR-3 cells. Downregulation of the ANKS1a expression with esiRNA had almost no effect on the cancer cell motility, except a slight increase in the average migration rate of MDA-MB-231 cells. Among three cell lines tested, overexpression of Anks1a increased the migration rate of HER2-overexpressng SK-BR-3 cells only. We showed that Anks1a is an effector of activated Rac1, but its influence on the cell migration in this capacity was minimal, at least in the studied breast cancer cells. Anks1a affected the motility of breast cancer cells due to its involvement in the EGF receptor exchange.

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Abbreviations

Anks1a:

ankyrin repeat and sterile alpha motif domain containing 1A

EGF:

epidermal growth factor

HER2:

human epidermal growth factor receptor 2

RTK:

receptor tyrosine kinase

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Funding

This study was conducted within the framework of the International Associated Laboratory (LIA) research project “Novel machineries controlling cell migration and their role in cancer progression” (MIG MAC) and supported by the Russian Foundation for Basic Research (project no. 18-54-16006 to A. Y. A).

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Authors and Affiliations

  1. N. N. Blokhin National Medical Research Center of Oncology, 115478, Moscow, Russia

    Anna O. Zholudeva, Maria E. Lomakina, Evgeniya A. Orlova & Antonina Y. Alexandrova

  2. CNRS UMR 7654, Ecole Polytechnique, Institut Polytechnique de Paris, Palaiseau, France

    Maria E. Lomakina, Yanan Wang, Artem I. Fokin, Anna Polesskaya & Alexis M. Gautreau

Authors
  1. Anna O. Zholudeva
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  2. Maria E. Lomakina
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  3. Evgeniya A. Orlova
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  4. Yanan Wang
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  5. Artem I. Fokin
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  6. Anna Polesskaya
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  7. Alexis M. Gautreau
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  8. Antonina Y. Alexandrova
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Contributions

A. Y. Alexandrova and A. M. Gautreau developed the concept and supervised the study; A. O. Zholudeva, M. E. Lomakina, E. A. Orlova, Y. Wang, A. Fokin, and A. Polesskaya performed the experiments; A. Y. Alexandrova, A. M. Gautreau, A. O. Zholudeva, M. E. Lomakina, A. Fokin, A. Polesskaya discussed the results; A. Y. Alexandrova, A. O. Zholudeva, M. E. Lomakina, A. Fokin wrote and edited the text.

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Correspondence to Antonina Y. Alexandrova.

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The authors declare no conflict of interest. This article does not contain description of studies with human participants or animals performed by any of the authors.

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Zholudeva, A.O., Lomakina, M.E., Orlova, E.A. et al. The Role of the Adapter Protein Anks1a in the Regulation of Breast Cancer Cell Motility. Biochemistry Moscow 87, 1651–1661 (2022). https://doi.org/10.1134/S0006297922120203

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