ErbB2, EphrinB1, Src Kinase and PTPN13 Signaling Complex Regulates MAP Kinase Signaling in Human Cancers

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.

Targeting ERBB Receptors Shifts Their Partners and Triggers Persistent ERK Signaling through a Novel ERBB/EFNB1 Complex

“…Figure 1C demonstrates positive PLA signals for EFNB1 and ERBB1 in SCC1 (HPV−) and SCC47 (HPV+) cells. The previously discovered ERBB2/EFNB1 association (14) was confirmed and the presence of ERBB1/ERBB2 heterodimers was determined (Fig. 1C).…”

“…EFNB1 mutant constructs and PTPN13 C/S has been previously described (6, 14). Wildtype human ERBB1 cDNA was obtained from Addgene (#11011, Cambridge, MA) and cloned by PCR into pCMV-HA (Clontech).…”

“…Thus, in tumors with impaired PTPN13 expression or function, EFNB1 signaling may persist. In addition, Ephrin ligands are promiscuous in their associations (12, 13); for example, EFNB1 interacts with ERBB2 (14). Moreover, EFNB1 activation correlates with phosphorylation of ERK1/2 (14).…”

“…In addition, Ephrin ligands are promiscuous in their associations (12, 13); for example, EFNB1 interacts with ERBB2 (14). Moreover, EFNB1 activation correlates with phosphorylation of ERK1/2 (14). Together, these studies suggest that the complex consisting of ERBB2/EFNB1 together with PTPN13 regulates intracellular signals critical for epithelial tumorigenesis.…”

Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis

“…However, a recent study has shown that enhanced expression of ephrinB1 is associated with lymph node metastasis and poor prognosis in breast cancer (52). The authors did not propose a mechanism to explain the association between ephrinB1 and poor patient survival, but another recent study has shown that ephrinB1 is a substrate for PTEN and interacts with the tyrosine kinase receptor HER2 (or ErbB2) (53). Interestingly, breast tumors overexpressing HER2 are prone to metastasize to the brain (7) and therefore an association of HER2 with ephrinB1 could be a driver of brain metastasis.…”