Phosphorylation of plectin by Akt3 promotes triple-negative breast cancer cell invasive migration

  • iScience. 2025 Sep 12;28(10):113552. doi: 10.1016/j.isci.2025.113552.
Shixue Zheng  1  2 ,  Chloe Chan  1 ,  John M Asara  3 ,  Liang Zhang  1 ,  Gerhard Wiche  4 ,  Y Rebecca Chin  1
Affiliations
  • 1. Tung Biomedical Sciences Centre and Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Kowloon, Hong Kong.
  • 2. Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
  • 3. Department of Medicine, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • 4. Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.
PMID: 41079612 DOI: 10.1016/j.isci.2025.113552
Abstract

Triple-negative breast Cancer (TNBC) lacks targeted therapeutics and is aggressive with a poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, frequently deregulated in cancers, plays crucial roles in tumorigenesis and Cancer progression. However, the distinct functions of the three Akt isoforms (Akt1, Akt2, Akt3) in these processes are not well understood. Here, we focus on Akt3, the least-studied Akt isoform, which is overexpressed in 28% of TNBC cases and significantly promotes TNBC growth, stemness, and epithelial-mesenchymal transition. Through a genome-wide proteomic screen, we identified plectin, a member of the plakin family, as an Akt3 substrate in TNBC cells. The depletion of plectin potently inhibits TNBC cell migration and invadopodia formation, albeit with mild effects on cell growth. The phosphorylation of plectin at Ser4268 by Akt promotes its colocalization with vimentin and TNBC cell migration. Our findings underscore the importance of Akt3-plectin signaling as a potential TNBC therapeutic target.

Keywords
Biochemistry; Cancer; Proteomics.
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