A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

W. David Tolbert, Jennifer Daugherty, Chong Feng Gao, Qian Xie, Cindy Miranti, Ermanno Gherardi, George Vande Woude, H. Eric Xu

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.

Original languageEnglish (US)
Pages (from-to)14592-14597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 11 2007
Externally publishedYes


  • Cancer therapy
  • Heparin
  • Hepatocyte growth factor
  • Met antagonist
  • Tumor metastasis

ASJC Scopus subject areas

  • General


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