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J. Biol. Chem., Vol. 280, Issue 3, 1982-1991, January 21, 2005

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Regulated Association of Protein Kinase B/Akt with Breast Tumor Kinase^*

Ping Zhang, Julie Hanson Ostrander, Emily J. Faivre, Abby Olsen, Daniel Fitzsimmons, and Carol A. Lange

From the University of Minnesota Cancer Center and the Departments of Medicine, Division of Hematology, Oncology, and Transplantation, and Pharmacology, Minneapolis, Minnesota 55455

Increased protein-tyrosine kinase activity is a prognostic indicator of decreased disease-free survival in patients with advanced breast tumors. Breast tumor kinase (Brk) is a soluble protein-tyrosine kinase overexpressed in the majority of breast cancers and also in normal skin and gut epithelium, but not in normal breast epithelial cells. Herein, we show that Brk interacts with protein kinase B/Akt, a serine/threonine kinase involved in cell growth and survival. Epidermal growth factor (EGF) treatment of human keratinocytes or Brk-transfected COS-1 cells leads to the dissociation of the Brk·Akt complex, whereas a constitutively active Brk mutant containing a point mutation at Tyr-447 (YF-Brk) failed to dissociate from Akt upon EGF treatment. In addition, Brk·Akt dissociation was blocked by the inhibition of phosphatidylinositol 3-kinase. Similar to ectopic Brk, endogenous Brk in T47D breast cancer cells was less phosphorylated upon EGF treatment, but it remained constitutively associated with Akt in the presence of EGF. Overexpression of wild-type (wt)-Brk, kinase-inactive (KM)-Brk, or YF-Brk increased the Tyr phosphorylation of multiple signaling molecules including EGF receptor. However, only wt- and YF-Brk, but not KM-Brk, induced phosphorylation of Akt and inhibited the kinase activity of Akt in unstimulated cells. Similarly, overexpression of wt- or YF-, but not KM-Brk, blocked the phosphorylation of the forkhead transcription factor, a downstream Akt target. These results suggest that Brk may function as a signaling molecule whose kinase activity normally limits the activity of Akt in unstimulated cells. Additionally, these results suggest that in breast cancer cells Brk behaves similarly to a constitutively active Brk mutant (YF-Brk) and associates with tyrosine-phosphorylated proteins in deregulated signaling complexes. Together these data provide clues to the possible proto-oncogenic and oncogenic functions of Brk.

Received for publication, October 25, 2004 , and in revised form, November 10, 2004.

^* This work was supported by National Institutes of Health Grant R21DK058347 and American Cancer Society Grant RSG TBE-107800 (to C. A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of Minnesota Cancer Center, 420 Delaware St. SE., MMC 806, Minneapolis, MN 55455. Tel.: 612-626-0621; Fax: 612-626-4915; E-mail: Lange047{at}tc.umn.edu.

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