Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells

J Biol Chem. 2010 Dec 3;285(49):38093-103. doi: 10.1074/jbc.M110.162388. Epub 2010 Oct 7.

Abstract

STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • HeLa Cells
  • Humans
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / genetics
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Neoplasm Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • STAP2 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Protein-Tyrosine Kinases
  • PTK6 protein, human