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PMID:22897854

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Citation

Cecchi, F, Pajalunga, D, Fowler, CA, Uren, A, Rabe, DC, Peruzzi, B, Macdonald, NJ, Blackman, DK, Stahl, SJ, Byrd, RA and Bottaro, DP (2012) Targeted disruption of heparan sulfate interaction with hepatocyte and vascular endothelial growth factors blocks normal and oncogenic signaling. Cancer Cell 22:250-62

Abstract

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.

Links

PubMed PMC3422512 Online version:10.1016/j.ccr.2012.06.029

Keywords

Animals; Antigens, CD34/metabolism; Cell Proliferation/drug effects; Cluster Analysis; Dogs; Enzyme Activation/drug effects; Gene Targeting; Heparitin Sulfate/metabolism; Hepatocyte Growth Factor/antagonists & inhibitors; Hepatocyte Growth Factor/chemistry; Hepatocyte Growth Factor/metabolism; Humans; Magnetic Resonance Spectroscopy; Mice; Neoplasm Metastasis; Neoplasms/blood supply; Neoplasms/metabolism; Neoplasms/pathology; Neovascularization, Pathologic/metabolism; Neovascularization, Pathologic/pathology; Protein Binding/drug effects; Protein Folding/drug effects; Protein Isoforms/antagonists & inhibitors; Protein Isoforms/chemistry; Protein Isoforms/metabolism; Protein Multimerization/drug effects; Proto-Oncogene Proteins c-met/metabolism; Signal Transduction/drug effects; Vascular Endothelial Growth Factor A/antagonists & inhibitors; Vascular Endothelial Growth Factor A/metabolism; Vascular Endothelial Growth Factor A/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NRP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692-4

F

Seeded From UniProt

complete

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14210-6

F

Seeded From UniProt

complete

HUMAN:HGF

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete

HUMAN:NRP1

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692-4

F

Seeded From UniProt

complete

HUMAN:NRP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14786-2

F

Seeded From UniProt

complete

HUMAN:NRP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

F

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692-4

F

Seeded From UniProt

complete

HUMAN:VEGFA

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15692-4

F

Seeded From UniProt

complete

HUMAN:HGF

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14210-6

F

Seeded From UniProt

complete


See also

References

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