Abstract
In non-cancerous cells, phosphorylated proteins exist transiently, becoming de-phosphorylated by specific phosphatases that terminate propagation of signaling pathways. In cancers, compromised phosphatase activity and/or expression occur and contribute to tumor phenotype. The non-receptor phosphatase, PTPN13, has recently been dubbed a putative tumor suppressor. It decreased expression in breast cancer correlates with decreased overall survival. Here we show that PTPN13 regulates a new signaling complex in breast cancer consisting of ErbB2, Src, and EphrinB1. To our knowledge, this signaling complex has not been previously described. Co-immunoprecipitation and localization studies demonstrate that EphrinB1, a PTPN13 substrate, interacts with ErbB2. In addition, the oncogenic V660E ErbB2 mutation enhances this interaction, while Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. Decreased PTPN13 function further enhances signaling. The association of oncogene kinases (ErbB2, Src), a signaling transmembrane ligand (EphrinB1) and a phosphatase tumor suppressor (PTPN13) suggest that EphrinB1 may be a relevant therapeutic target in breast cancers harboring ErbB2-activating mutations and decreased PTPN13 expression.
Highlights
ErbB2 (Her2) amplification/over-expression occurs in 20-30% of breast cancers resulting in aggressive tumor behavior and poor prognosis [1,2]
PTPN13 knock-down did not affect Erk1/2 phosphorylation, suggesting that either EphrinB1 does not signal via the MAP Kinase pathway in MDA-MB468 cells or that its signaling is modulated in these cells via additional components
We describe a complex consisting of ErbB2, Src, EphrinB1 and PTPN13 that mediates EphrinB1 phosphorylation and downstream signaling in breast cancer cells
Summary
ErbB2 (Her2) amplification/over-expression occurs in 20-30% of breast cancers resulting in aggressive tumor behavior and poor prognosis [1,2]. ErbB2 activation via hetero-dimerization with other family members or homo-dimerization with itself (when expressed at high levels) initiates intracellular signals that culminate in transcription of many genes regulating proliferation, survival, differentiation, invasion and metastasis In this way, ErbB2 plays a key role in orchestrating an aggressive breast cancer phenotype [3]. While significant progress has been made in understanding the role of ErbB2 in breast cancer initiation and progression, the overwhelming resistance to trastuzumab therapy suggests that additional signaling pathways exist that circumvent ErbB2 antibody-mediated blockade Characterizing these pathways and, more importantly, the proteins that initiate them, will define novel targets for therapeutic intervention that may re-sensitize Her patients to trastuzumab and improve survival
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