The heparin-binding domain of heparin-binding EGF-like growth factor can target Pseudomonas exotoxin to kill cells exclusively through heparan sulfate proteoglycans

Enrique A Mesri, Minoru Ono, Robert J. Kreitman, Michael Klagsbrun, Ira Pastan

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Heparin-binding EGF-like growth factor (HB-EGF) is a smooth muscle cell mitogen composed of both EGF receptor and heparin-binding domains. To better understand the function of its domains, intact HB-EGF or its heparin-binding (HB) domain (amino acids 1-45) were fused to a mutant Pseudomonas exotoxin with an inactivated cell-binding domain. The resulting chimeric toxins, HB-EGF-PE(*) and HB-PE(*), were tested on tumor cells, proliferating smooth muscle cells and a mutant Chinese hamster ovary cell line deficient in heparan sulfate proteoglycans (HSPGs). Two targets were found for HB-EGF-PE(*). Cells were killed mainly through EGF receptors, but the HB domain was responsible for killing via HSPGs. HB-PE(*) did not bind to the EGF receptor and thus was cytotoxic by interacting exclusively with HSPGs. We conclude that the HB domain of HB-EGF is able to mediate internalization through HSPGs, without requiring the EGF receptor.

Original languageEnglish
Pages (from-to)2599-2608
Number of pages10
JournalJournal of Cell Science
Volume107
Issue number9
StatePublished - Sep 1 1994
Externally publishedYes

Fingerprint

Exotoxins
Heparan Sulfate Proteoglycans
Pseudomonas
Heparin
Epidermal Growth Factor Receptor
Smooth Muscle Myocytes
Immunotoxins
Cricetulus
Mitogens
Heparin-binding EGF-like Growth Factor
Ovary
Amino Acids
Cell Line
Neoplasms

Keywords

  • Antitumor agents
  • Cancer cells
  • Heparin
  • Immunotoxins
  • Pseudomonas exotoxin A
  • Smooth muscle cells

ASJC Scopus subject areas

  • Cell Biology

Cite this

The heparin-binding domain of heparin-binding EGF-like growth factor can target Pseudomonas exotoxin to kill cells exclusively through heparan sulfate proteoglycans. / Mesri, Enrique A; Ono, Minoru; Kreitman, Robert J.; Klagsbrun, Michael; Pastan, Ira.

In: Journal of Cell Science, Vol. 107, No. 9, 01.09.1994, p. 2599-2608.

Research output: Contribution to journalArticle

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AB - Heparin-binding EGF-like growth factor (HB-EGF) is a smooth muscle cell mitogen composed of both EGF receptor and heparin-binding domains. To better understand the function of its domains, intact HB-EGF or its heparin-binding (HB) domain (amino acids 1-45) were fused to a mutant Pseudomonas exotoxin with an inactivated cell-binding domain. The resulting chimeric toxins, HB-EGF-PE(*) and HB-PE(*), were tested on tumor cells, proliferating smooth muscle cells and a mutant Chinese hamster ovary cell line deficient in heparan sulfate proteoglycans (HSPGs). Two targets were found for HB-EGF-PE(*). Cells were killed mainly through EGF receptors, but the HB domain was responsible for killing via HSPGs. HB-PE(*) did not bind to the EGF receptor and thus was cytotoxic by interacting exclusively with HSPGs. We conclude that the HB domain of HB-EGF is able to mediate internalization through HSPGs, without requiring the EGF receptor.

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