Tyrosine kinase signaling in cancer cells

 

Our group is interested in understanding the basis for deregulated kinase signaling in cancer cells. Brk (breast tumor kinase) was identified by Mark Crompton's group in a study of kinase expression in human metastatic breast tumors. Brk expression was low or undetectable in normal mammary tissues or in benign lesions. However, approximately two-thirds of the breast tumors that were examined overexpressed Brk. Brk is a member of the Frk family of nonreceptor tyrosine kinases. Brk possesses SH3, SH2, and catalytic domains in a similar arrangement to that of Src family kinases. Using purified Brk, we showed that the enzyme is regulated by autophosphorylation at Tyr342 and by intramolecular interactions involving the SH3 and SH2 domains. We used a proteomic strategy to identify Brk-interacting partners.

For more details, see:

H. Qiu & W.T. Miller (2002). Regulation of the nonreceptor tyrosine kinase Brk by autophosphorylation and by autoinhibition. J. Biol. Chem. 277, 34634-34641.

H. Qiu & W.T. Miller (2004). Role of the Brk SH3 domain in substrate recognition. Oncogene 23, 2216-2223.

H. Qiu, F. Zappaosta, W. Su, R.S. Annan, and W.T. Miller (2005). Interaction between Brk kinase and insulin receptor substrate-4. Oncogene 24, 5656-5664.

L. Liu, Y. Gao, W.T. Miller, V. Poli, and N.C. Reich (2006). Identification of STAT3 as a specific substrate of the breast tumor kinase (Brk). Oncogene 25, 4904-4912.

 

In collaboration with Dr. Senthil Muthuswamy (Cold Spring Harbor), we recently showed that Brk and ErbB2 are co-amplified and co-overexpressed in human breast cancers. The two tyrosine kinases cooperate to promote proliferation of breast cancer cells, and coexpression of ErbB2 and Brk promotes tumor formation in an in vivo mouse mammary tumorigenesis model. Our current goal is to understand the biochemical basis for the synergy between the two tyrosine kinases.

 

For more details, see:

  B. Xiang, K. Chatti, H. Qiu, B. Lakshmi, A. Krasnitz, J. Hicks, W.T. Miller, and S.K. Muthuswamy (2008). Brk is coamplified with ErbB2 to promote proliferation in breast cancer. Proc. Natl. Acad. Sci. USA. 105, 12463-12468.