Identification of STAT3 as a specific substrate of breast tumor kinase

Abstract

Breast tumor kinase (Brk) is a non-receptor tyrosine kinase distantly related to the Src family kinase. It is expressed in more than 60% of breast tumors, but the biological role of this kinase remains to be determined. Only a limited number of substates have been identified for Brk, and the link of Brk to tumorigenesis remains largely unknown. In this study, we provide evidence that the signal transducer and activator of transcription 3, STAT3, is a physiological target of Brk. Activation of STAT3 previously has been linked to oncogenesis, and results in this study demonstrate that STAT3 is tyrosine phosphorylated and transcriptionally activated in cells expressing endogenous Brk. Signal transducer and activator of transcription 3 is specifically targeted since other STAT members are not responsive to Brk expression. Signal transducer and activator of transcription 3 activation requires the catalytic activity of Brk, and expression of both STAT3 and Brk stimulate cellular proliferation. In addition, we have identified a negative regulator of Brk, the suppressor of cytokine signaling, SOCS3. The SOCS3 protein is known to block signaling mediated by cytokine receptors, and here we find that SOCS3 is able to repress the activity of the Brk nonreceptor tyrosine kinase.

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

“…In addition, here, we could show that also PTEN, which belongs to the same PI3K/Akt signalling pathway, coprecipitates with PTK6 in T47D cell line, and is statistically associated with the expression of PTK6 in tumour tissue. PTK6 influences the MAPK pathway (as described above), and there is evidence that STATs are also physiological targets of PTK6 (Liu et al, 2006;Weaver and Silva, 2007). This obvious involvement of PTK6 in all three signalling pathways may be explained to some extent by cross talk between pathways.…”

“…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).…”

STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation

“…We next tested whether activation of Brk is required for a direct interaction with STAP- Importantly, recent studies have shown that STAT3 is a Brk substrate and that Brk activates STAT3 [17]. STAT3 is known to act as an oncogene in a constitutively active form, and phosphorylation and activation of STAT3 is correlated with breast cancer [18,19,20].…”

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

“…STAT3 and STAT5, which play crucial roles in cell proliferation and differentiation, are also believed to be activated by BRK (Liu et al, 2006;Weaver and Silva, 2007). Our previous studies demonstrate that STAP-2 interacts with and influences several signaling molecules, including STAT3 and STAT5.…”

“…BRK substrates include RNA-binding proteins (Sam68 (Coyle et al, 2003;Derry et al, 2000;Lukong et al, 2005), SLM-1/2 (Haegebarth et al, 2004), and the polypyrimidine tractbinding protein-associated splicing factor (PSF) (Lukong et al, 2009)), transcription factors (STAT3 (Liu et al, 2006) and STAT5A/B (Weaver and Silva, 2007)), adaptor molecules (STAP-2) (Mitchell et al, 2000), and a variety of signaling molecules (paxillin (Chen et al, 2004), p190RhoGAP (Shen et al, 2008), kinesin-associated protein 3A (KAP3A) (Lukong and Richard, 2008), Akt (Zhang et al, 2005), -catenin (Palka-Hamblin et al, 2010), and ARAP1 (Arf-GAP, Rho-GAP, ankyrin repeat and PH domain-containing protein 1; also known as centaurin δ-2) (Kang et al, 2010)). Although BRK expression is known to induce tyrosine phosphorylation in some of these, similar actions in others have yet to be confirmed.…”