Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells
- 1 May 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (9), 4199-4209
- https://doi.org/10.1158/0008-5472.can-06-3409
Abstract
Total tyrosine kinase activity is often elevated in both cytosolic and membrane fractions of malignant breast tissue and correlates with a decrease in disease-free survival. Breast tumor kinase (Brk; protein tyrosine kinase 6) is a soluble tyrosine kinase that was cloned from a metastatic breast tumor and found to be overexpressed in a majority of breast tumors. Herein, we show that Brk is overexpressed in 86% of invasive ductal breast tumors and coexpressed with ErbB family members in breast cancer cell lines. Additionally, the ErbB ligand, heregulin, activates Brk kinase activity. Knockdown of Brk by stable expression of short hairpin RNA (shRNA) in T47D breast cancer cells decreases proliferation and blocks epidermal growth factor (EGF)- and heregulin-induced activation of Rac GTPase, extracellular signal-regulated kinase (ERK) 5, and p38 mitogen-activated protein kinase (MAPK) but not Akt, ERK1/2, or c-Jun NH2-terminal kinase. Furthermore, EGF- and heregulin-induced cyclin D1 expression is dependent on p38 signaling and inhibited by Brk shRNA knockdown. The myocyte enhancer factor 2 transcription factor target of p38 MAPK and ERK5 signaling is also sensitive to altered Brk expression. Finally, heregulin-induced migration of T47D cells requires p38 MAPK activity and is blocked by Brk knockdown. These results place Brk in a novel signaling pathway downstream of ErbB receptors and upstream of Rac, p38 MAPK, and ERK5 and establish the ErbB-Brk-Rac-p38 MAPK pathway as a critical mediator of breast cancer cell migration. [Cancer Res 2007;67(9):4199–209]Keywords
This publication has 51 references indexed in Scilit:
- Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small IntestineMolecular and Cellular Biology, 2006
- Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK SignalingMolecular and Cellular Biology, 2006
- Activation of ErbB2 by Overexpression or by Transmembrane Neuregulin Results in Differential Signaling and Sensitivity to HerceptinCancer Research, 2005
- p38 Regulates Cyclooxygenase-2 in Human Mammary Epithelial Cells and Is Activated in Premalignant TissueCancer Research, 2005
- Breast cancer cells with inhibition of p38<>α have decreased MMP-9 activity and exhibit decreased bone metastasis in miceClinical & Experimental Metastasis, 2004
- The activities of cyclin D1 that drive tumorigenesisTrends in Molecular Medicine, 2004
- Rac–MEKK3–MKK3 scaffolding for p38 MAPK activation during hyperosmotic shockNature, 2003
- Activation of cyclin D1 expression by the ERK5 cascadeOncogene, 2003
- Big Mitogen-activated Kinase Regulates Multiple Members of the MEF2 Protein FamilyPublished by Elsevier BV ,2000
- Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic miceNature, 1994