Potent Blockade of Hepatocyte Growth Factor-stimulated Cell Motility, Matrix Invasion and Branching Morphogenesis by Antagonists of Grb2 Src Homology 2 Domain Interactions

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical signals that regulate these events. Multiple signaling proteins are phosphorylated in epithelial cells during hepatocyte growth factor–induced cell dispersal, including c-Cbl, a protooncogene docking protein with ubiquitin ligase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cbl) in epithelial cell dispersal. We show that the expression of 70z-Cbl in Madin-Darby canine kidney epithelial cells resulted in the breakdown of cell–cell contacts and alterations in cell morphology characteristic of epithelial–mesenchymal transition. Structure–function studies revealed that the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosphotyrosine-binding/Src homology domain 2 , is sufficient to promote the morphological changes in cell shape. Moreover, a point mutation at Gly-306 abrogates the ability of the Cbl Src homology domain 2 to induce these morphological changes. Our results identify a role for Cbl in the regulation of epithelial–mesenchymal transition, including loss of adherens junctions, cell spreading, and the initiation of cell dispersal.

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Nuclear Magnetic Resonance Solution Structure of the Growth Factor Receptor-Bound Protein 2 Src Homology 2 Domain

Biochemistry ◽

10.1021/bi952615s ◽

1996 ◽

Vol 35 (36) ◽

pp. 11852-11864 ◽

Cited By ~ 12

Author(s):

Kevin H. Thornton ◽

W. Tom Mueller ◽

Patrick McConnell ◽

Guochang Zhu ◽

Alan R. Saltiel ◽

...

Keyword(s):

Nuclear Magnetic Resonance ◽

Growth Factor ◽

Magnetic Resonance ◽

Solution Structure ◽

Growth Factor Receptor ◽

Src Homology 2 ◽

Resonance Solution ◽

Src Homology ◽

Src Homology 2 Domain ◽

Growth Factor Receptor Bound

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Hepatocyte growth factor-induced endothelial cell motility is mediated by the upregulation of inducible nitric oxide synthase expression

Cardiovascular Research ◽

10.1016/s0008-6363(02)00255-9 ◽

2002 ◽

Vol 54 (3) ◽

pp. 659-668 ◽

Cited By ~ 22

Author(s):

K Purdie

Keyword(s):

Nitric Oxide ◽

Endothelial Cell ◽

Growth Factor ◽

Nitric Oxide Synthase ◽

Hepatocyte Growth Factor ◽

Cell Motility ◽

Inducible Nitric Oxide Synthase ◽

Oxide Synthase ◽

Hepatocyte Growth ◽

Inducible Nitric Oxide

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SRC-homology 2 domain-containing phosphatase 2 (SHP2) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9540 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9540-9540

Author(s):

Rafael Rosell ◽

Masaoki Ito ◽

Jordi Codony-Servat ◽

Ana Giménez-Capitán ◽

Mireia Serra-Mitjans ◽

...

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Mrna Expression ◽

Mrna Levels ◽

Wild Type ◽

Src Homology 2 ◽

Src Homology ◽

Epidermal Growth ◽

Src Homology 2 Domain ◽

Egfr Mutant

9540 Background: Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts). Methods: We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2. Results: Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio = 1.83 and 2.28, respectively. p = 0.03 and p = 0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib translocates SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocalizes SHP2 into the cytoplasm membrane, limiting AKT and ERK activation. Conclusions: High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.

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