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 language | English |
|---|---|
| Pages (from-to) | 5090-5095 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 13 |
| DOIs | |
| Publication status | Published - Mar 28 2006 |
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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 journal › Article
}
TY - JOUR
T1 - Ab-induced ectodomain shedding mediates hepatocytes growth factor receptor down-regulation and hampers biological activity
AU - Petrelli, Annalisa
AU - Circosta, Paola
AU - Granziero, Luisa
AU - Mazzone, Massimiliano
AU - Pisacane, Alberto
AU - Fenoglio, Silvia
AU - Comoglio, Paolo M.
AU - Giordano, Silvia
PY - 2006/3/28
Y1 - 2006/3/28
N2 - 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.
AB - 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.
KW - Ab
KW - Metastasis
KW - Proteolytic cleavage
KW - Receptor degradation
KW - Tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=33645518840&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645518840&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508156103
DO - 10.1073/pnas.0508156103
M3 - Article
C2 - 16547140
AN - SCOPUS:33645518840
VL - 103
SP - 5090
EP - 5095
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 13
ER -