Title: Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity
Authors: Petrelli, A
Circosta, P
Granziero, L
Mazzone, Massimiliano
Pisacane, A
Fenoglio, S
Comoglio, PM
Giordano, S # ×
Issue Date: Mar-2006
Publisher: Natl acad sciences
Series Title: Proceedings of the national academy of sciences of the united states of america vol:103 issue:13 pages:5090-5095
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 FGF-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.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Tumor Inflammation and Angiogenesis (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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