Ab-induced ectodomain shedding mediates hepatocytes growth factor receptor down-regulation and hampers biological activity

Annalisa Petrelli, Paola Circosta, Luisa Granziero, Massimiliano Mazzone, Alberto Pisacane, Silvia Fenoglio, Paolo M. Comoglio, Silvia Giordano

Research output: Contribution to journalArticle

Abstract

Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs' biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro, chronic treatment of carcinoma cell lines resulted in impairment of HGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo, administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nu/nu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: (i) cleavage of the extracellular portion, resulting in "shedding" of the ectodomain, and (ii) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the "decoy effect" generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.

Original languageEnglish
Pages (from-to)5090-5095
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number13
DOIs
Publication statusPublished - Mar 28 2006

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Proto-Oncogene Proteins c-met
Hepatocyte Growth Factor
Down-Regulation
Receptor Protein-Tyrosine Kinases
Proteasome Endopeptidase Complex
Growth
Signal Transduction
Carcinoma
Cell Line
Lung
Neoplasms
Therapeutics
In Vitro Techniques

Keywords

  • Ab
  • Metastasis
  • Proteolytic cleavage
  • Receptor degradation
  • Tyrosine kinase

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Ab-induced ectodomain shedding mediates hepatocytes growth factor receptor down-regulation and hampers biological activity. / Petrelli, Annalisa; Circosta, Paola; Granziero, Luisa; Mazzone, Massimiliano; Pisacane, Alberto; Fenoglio, Silvia; Comoglio, Paolo M.; Giordano, Silvia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 13, 28.03.2006, p. 5090-5095.

Research output: Contribution to journalArticle

Petrelli, Annalisa ; Circosta, Paola ; Granziero, Luisa ; Mazzone, Massimiliano ; Pisacane, Alberto ; Fenoglio, Silvia ; Comoglio, Paolo M. ; Giordano, Silvia. / Ab-induced ectodomain shedding mediates hepatocytes growth factor receptor down-regulation and hampers biological activity. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 13. pp. 5090-5095.
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AU - Pisacane, Alberto

AU - Fenoglio, Silvia

AU - Comoglio, Paolo M.

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