EphrinB1: novel microtubule associated protein whose expression affects taxane sensitivity

Abstract

Microtubules (MTs) are components of the cytoskeleton made up of polymerized alpha and beta tubulin dimers. MT structure and function must be maintained throughout the cell cycle to ensure proper execution of mitosis and cellular homeostasis. The protein tyrosine phosphatase, PTPN13, localizes to distinct compartments during mitosis and cytokinesis. We have previously demonstrated that the HPV16 E6 oncoprotein binds PTPN13 and leads to its degradation. Thus, we speculated that HPV infection may affect cellular proliferation by altering the localization of a PTPN13 phosphatase substrate, EphrinB1, during mitosis. Here we report that EphrinB1 co-localizes with MTs during all phases of the cell cycle. Specifically, a cleaved, unphosphorylated EphrinB1 fragment directly binds tubulin, while its phosphorylated form lacks MT binding capacity. These findings suggest that EphrinB1 is a novel microtubule associated protein (MAP). Importantly, we show that in the context of HPV16 E6 expression, EphrinB1 affects taxane response in vitro. We speculate that this reflects PTPN13's modulation of EphrinB1 phosphorylation and suggest that EphrinB1 is an important contributor to taxane sensitivity/resistance phenotypes in epithelial cancers. Thus, HPV infection or functional mutations of PTPN13 in non-viral cancers may predict taxane sensitivity.

EphrinB1 promotes cancer cell migration and invasion through the interaction with RhoGDI1

“…EphrinB1 reverse signaling is implicated in regulating cell migration, cell invasion, angiogenesis, metastatic progression of cancer cells, and chemoresistance. 5 , 45 The intracellular domain of ephrinB1 contains docking sites for various signaling components that have a pivotal role in cell migration. Here, we show that the stimulation of ephrinB1 by EphB2-Fc promotes migration and invasion of cancer cells through RhoA activity.…”

Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer

“…Ephrin B1 also is implicated in the response to anti-tumor treatments. Indeed, when dephosphorylated, ephrin B1 can bind to mitotic spindle microtubules, thus increasing the sensitivity to paclitaxel in head and neck squamous cell carcinoma and breast cancer cell lines [ 132 ]. Conversely, when phosphorylated, ephrin B1 is excluded from the spindle and is associated with resistance to paclitaxel in epithelial cancer cell lines.…”

“…Conversely, when phosphorylated, ephrin B1 is excluded from the spindle and is associated with resistance to paclitaxel in epithelial cancer cell lines. Ephrin B1 dephosphorylation is directly regulated by PTPN13, and this may explain why tumors with low PTPN13 expression are resistant to paclitaxel [ 132 ].…”