Function and mutual interaction of BiP-, PERK-, and IRE1α-dependent signalling pathways in vascular tumours

Laura Anspach, Roman Tsaryk, Larissa Seidmann, Ronald E. Unger, Caren Jayasinghe, Nektaria Simiantonaki, C. James Kirkpatrick, Felicitas Pröls

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of binding immunoglobulin protein (BIP) and PERK with concomitant attenuated IRE1α levels, whereas haemangioma tissue exhibits the same pattern as embryonal skin tissue. We show that BiP is essential for the maintenance of VEGFR2 protein, which is expressed in the endothelium of both tumour types. When studying the effects of BiP, the IRE1α/Xbp1 -, and PERK/ATF4-signalling pathways on the migration and tube-forming potential of endothelial cells, we show that downregulation of BiP, as well as inhibition of the kinase activity of IRE1α, inhibit in vitro angiogenesis. Downregulation of PERK (PKR-like kinase; PKR = protein kinase R) levels promotes Xbp1 splicing in endoplasmic reticulum (ER)-stressed cells, indicating that in angiosarcoma the elevated PERK levels might result in high levels of unspliced Xbp1, which have been reported to promote cell proliferation and increase tumour malignancy. The data presented in this study revealed that in addition to BiP or PERK, the kinase domains of IRE1α and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis.

Original languageEnglish
Pages (from-to)123-134
Number of pages12
JournalJournal of Pathology
Issue number2
StatePublished - 1 Jun 2020
Externally publishedYes

Bibliographical note

Funding Information:
SubAB and the mutant SubA272B were kindly provided by J.C. Paton, Research Centre for Infectious Diseases, Department of Molecular and Biomedical Science, University of Adelaide, South Australia. The excellent technical assistance of Valentina Dörl is gratefully acknowledged.

Publisher Copyright:
© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


  • VEGFR2
  • angiosarcoma
  • chaperone
  • haemangioma
  • tumour angiogenesis
  • unfolded protein response, crosstalk


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