Abstract
Hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of cellular targets during development, homeostasis and tissue regeneration. Inappropriate HGF signaling occurs in several human cancers, and the ability of HGF to initiate a program of protease production, cell dissociation, and motility has been shown to promote cellular invasion and is strongly linked to tumor metastasis. Upon HGF binding, several tyrosines within the intracellular domain of its receptor, c-Met, become phosphorylated and mediate the binding of effector proteins, such as Grb2. Grb2 binding through its SH2 domain is thought to link c-Met with downstream mediators of cell proliferation, shape change, and motility. We analyzed the effects of Grb2 SH2 domain antagonists on HGF signaling and observed potent blockade of cell motility, matrix invasion, and branching morphogenesis, with ED(50) values of 30 nm or less, but only modest inhibition of mitogenesis. These compounds are 1000-10,000-fold more potent anti-motility agents than any previously characterized Grb2 SH2 domain antagonists. Our results suggest that SH2 domain-mediated c-Met-Grb2 interaction contributes primarily to the motogenic and morphogenic responses to HGF, and that these compounds may have therapeutic application as anti-metastatic agents for tumors where the HGF signaling pathway is active.
Highlights
The biological responses to Hepatocyte growth factor (HGF) are mediated by its cell surface receptor, c-Met, a transmembrane tyrosine kinase
phosphoinositide 3-kinase (PI3K) activity is required for both HGF-stimulated scatter and mitogenesis [10, 11], Gab1 is sufficient for tubulogenesis [12], and Grb2 binding appears to be required for HGF-stimulated cell motility and branching tubulogenesis [13,14,15]
In addition to its mitogenic activity, the ability of HGF to initiate a program of cell dissociation and increased cell motility coupled with increased protease production has been shown to promote cellular invasion through extracellular matrix substrates, and is correlated with tumor metastasis in vivo
Summary
Vol 276, No 17, Issue of April 27, pp. 14308 –14314, 2001 Printed in U.S.A. Potent Blockade of Hepatocyte Growth Factor-stimulated Cell Motility, Matrix Invasion and Branching Morphogenesis by Antagonists of Grb Src Homology 2 Domain Interactions*. We analyzed the effects of Grb SH2 domain antagonists on HGF signaling and observed potent blockade of cell motility, matrix invasion, and branching morphogenesis, with ED50 values of 30 nM or less, but only modest inhibition of mitogenesis. Upon HGF binding, several tyrosines residues within the c-Met intracellular domain are phosphorylated, some of which are essential for catalytic activity, and some of which mediate the binding of signaling proteins such as the p85 subunit of phosphoinositide 3-kinase (PI3K), phospholipase C-␥, Shc, Gab, and Grb (reviewed in Ref. 9). Grb is thought to link HGF-stimulated c-Met activation with the activation of Rho, Ras, and Rac [17], and to regulate critical steps in early embryonic development, as well as in malignant transformation [31] We show that these compounds potently block HGF-stimulated cell motility, matrix invasion, and branching morphogenesis, but not HGF-stimulated mitogenesis, with ED50 values of 1–30 nM. Our results suggest that c-Met-Grb interaction contributes primarily to the motogenic and morphogenic cellular responses to HGF, and that these compounds may have therapeutic application as anti-metastatic drugs in tumors where the HGF signaling pathway is active
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