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UCS15A, a non-kinase inhibitor of Src signal transduction

S V Sharma1, C Oneyama, Y Yamashita

  • 1Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd. 3-6-6 Asahi-cho, Machida-shi, Tokyo 194, Japan.

Oncogene
|May 22, 2001
PubMed

Insights

A novel src-signal transduction inhibitor, UCS15A, was identified. It disrupts protein interactions, not kinase activity, to inhibit src signaling and osteoclast bone resorption.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Src tyrosine kinase is crucial for growth factor and adhesion signaling.
  • Defects in src signaling are linked to various human diseases.
  • Novel inhibitors are needed to target src-mediated signal transduction.

Purpose of the Study:

  • To develop a yeast-based system for identifying small molecule src inhibitors.
  • To identify and characterize a unique src-signal transduction inhibitor, UCS15A.

Main Methods:

  • Utilized a yeast-based, activated-src over-expression system for inhibitor screening.
  • Investigated UCS15A's effect on src-specific tyrosine phosphorylation in v-src-transformed cells.
  • Identified cortactin and Sam68 as UCS15A-affected src substrates.

Main Results:

  • Identified UCS15A as a novel src-signal transduction inhibitor.
  • UCS15A inhibits src-specific tyrosine phosphorylation of proteins, including cortactin and Sam68.
  • UCS15A does not inhibit src tyrosine kinase activity or destabilize src via Hsp90.

Conclusions:

  • UCS15A inhibits src signaling through a novel mechanism involving disruption of src-mediated protein-protein interactions.
  • UCS15A inhibits osteoclast bone resorption in vitro.
  • UCS15A represents a potential therapeutic agent by modulating src signaling pathways.

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