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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner

Author

  • Konstantinos S Papadakos
  • Alexander Ekström
  • Piotr Slipek
  • Eleni Skourti
  • Steven Reid
  • Kristian Pietras
  • Anna M Blom

Summary, in English

BACKGROUND: Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor.

METHODS: In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method.

RESULTS: We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells.

CONCLUSIONS: In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.

Department/s

  • LUCC: Lund University Cancer Centre
  • Protein Chemistry, Malmö
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Experimental oncology
  • Division of Translational Cancer Research
  • Department of Translational Medicine

Publishing year

2022-12-29

Language

English

Pages

363-363

Publication/Series

Journal of Experimental and Clinical Cancer Research

Volume

41

Issue

1

Document type

Journal article

Publisher

BioMed Central (BMC)

Topic

  • Medicinal Chemistry
  • Cancer and Oncology

Keywords

  • Humans
  • Animals
  • Mice
  • Triple Negative Breast Neoplasms/metabolism
  • Phosphorylation
  • ErbB Receptors/genetics
  • Receptors, Growth Factor/metabolism
  • Autophagy
  • Cell Line, Tumor

Status

Published

Research group

  • Protein Chemistry, Malmö
  • Experimental oncology

ISBN/ISSN/Other

  • ISSN: 1756-9966