Targeted Disruption of Heparan Sulfate Interaction with Hepatocyte and Vascular Endothelial Growth Factors Blocks Normal and Oncogenic Signaling

被引：38

作者：

Cecchi, Fabiola ^{[1
]}

Pajalunga, Deborah ^{[2
,3
]}

Fowler, C. Andrew ^{[2
]}

Ueren, Aykut ^{[4
]}

Rabe, Daniel C. ^{[1
]}

Peruzzi, Benedetta ^{[1
]}

MacDonald, Nicholas J. ^{[3
]}

Blackman, Davida K. ^{[3
]}

Stahl, Stephen J. ^{[5
]}

Byrd, R. Andrew ^{[2
]}

Bottaro, Donald P. ^{[1
]}

机构：

[1] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA

[2] Frederick Natl Lab Canc Res, Macromol NMR Sect, Struct Biophys Lab, Frederick, MD 21702 USA

[3] EntreMed Inc, Rockville, MD 20850 USA

[4] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA

[5] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA

来源：

CANCER CELL | 2012年 / 22卷 / 02期

关键词：

CRYSTAL-STRUCTURE; FACTOR/SCATTER FACTOR; FACTOR ISOFORMS; NK1; FRAGMENT; C-MET; FUNCTIONAL-CHARACTERIZATION; PROVIDE INSIGHTS; STRUCTURAL BASIS; DOMAIN RECEPTOR; FACTOR REVEALS;

D O I：

10.1016/j.ccr.2012.06.029

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) regulate normal development and homeostasis and drive disease progression in many forms of cancer. Both proteins signal by binding to receptor tyrosine kinases and heparan sulfate (HS) proteoglycans on target cell surfaces. Basic residues comprising the primary HS binding sites on HGF and VEGF provide similar surface charge distributions without underlying structural similarity. Combining three acidic amino acid substitutions in these sites in the HGF isoform NK1 or the VEGF isoform VEGF165 transformed each into potent, selective competitive antagonists of their respective normal and oncogenic signaling pathways. Our findings illustrate the importance of HS in growth factor driven cancer progression and reveal an efficient strategy for therapeutic antagonist development.

引用

页码：250 / 262

页数：13

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