Breast Tumor Kinase (Protein Tyrosine Kinase 6) Regulates Heregulin-Induced Activation of ERK5 and p38 MAP Kinases in Breast Cancer Cells

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 heregulininduced activation of Rac GTPase, extracellular signalregulated kinase (ERK) 5, and p38 mitogen-activated protein kinase (MAPK) but not Akt, ERK1/2, or c-Jun NH 2 -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 ErbBBrk-Rac-p38 MAPK pathway as a critical mediator of breast cancer cell migration. [Cancer Res 2007;67(9):4199-209]

HIF-1α-independent hypoxia-induced rapid PTK6 stabilization is associated with increased motility and invasion

“…[1][2][3][4][5][6] In normal tissues, PTK6 expression is restricted to the differentiated epithelium of the skin and gut, while in tumors the highest levels of PTK6 expression correlate with higher tumor grade, larger size, metastasis, and consequently a poorer prognosis. [7][8][9] PTK6 has specific functions in different tissue types, including regulating differentiation in normal tissues and promoting proliferation and cell survival in tumors, brought about by variations in cellular localization. 1,10 PTK6 is activated by a number of different ligands, as well as displaying a small amount of basal auto-phosphorylation in in vitro kinase assays.…”

“…1,10 PTK6 is activated by a number of different ligands, as well as displaying a small amount of basal auto-phosphorylation in in vitro kinase assays. 11 EGF (epidermal growth factor) and IGF (insulin-like growth factor) induced signaling have been shown to activate PTK6, 9,12,13 as have HGF (hepatocyte growth factor) and osteopontin (OPN). 11,14 Radiation treatment has also been reported to lead to the induction of PTK6 in both mouse intestine epithelial cells and human colorectal cancer cells, however, little is known about the mechanisms that regulate the de novo expression of PTK6 in tumors.…”

Prognostic value of protein tyrosine kinase 6 (PTK6) for long-term survival of breast cancer patients

“…PTK6 was shown to be overexpressed in two-thirds of breast carcinomas (Mitchell et al, 1994;Barker et al, 1997;Llor et al, 1999;Born et al, 2005;Aubele et al, 2007;Ostrander et al, 2007), and expression is elevated in colon tumours and several cancer cell lines (Barker et al, 1997;Llor et al, 1999;Kamalati et al, 2000;Meric et al, 2002;Derry et al, 2003).…”

“…Many of these suggest a possible involvement of PTK6 in modulating signal transduction of HER receptor tyrosine kinases (Kamalati et al, 1996(Kamalati et al, , 2000Chen et al, 2004;Haegebarth et al, 2005;Zhang et al, 2005). Knockdown of PTK6 decreases proliferation in breast cancer cell lines (Harvey and Crompton, 2003) and blocks activity of a GTPase, of ERK5 (extracellular signal-regulated kinase) and p38 mitogenactivated protein kinase (MAPK), but not Akt (Mitchell et al, 1994;Barker et al, 1997;Llor et al, 1999;Born et al, 2005;Ostrander et al, 2007). Furthermore, PTK6 phosphorylates STAT3 (signal transducer and activator of transcription 3; Liu et al, 2006) and STAT 5b, leading to increased STAT 5b transcriptional activity in several breast cancer cell lines (Weaver and Silva, 2007).…”

Interactions of STAP-2 with BRK and STAT3/5 in Breast Cancer Cells

“…Importantly, over-expression of BRK sensitizes human mammary epithelial cells to EGF and/or heregulin stimuli, and increases anchorage-independent growth (Kamalati et al, 1996(Kamalati et al, , 2000, while down-regulation of BRK also influences EGF-and heregulin-induced cell proliferation. These observations suggest that BRK is involved in signaling induced by members of the EGFR family (Ostrander et al, 2007). Notably, BRK interacts with additional ErbB family members (ErbB2, ErbB3, and ErbB4) as well as EGFR (ErbB1) (Kamalati et al, 1996;Aubele et al, 2007;Xiang et al, 2008).…”