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EphrinB1 Interacts with CNK1 and Promotes Cell Migration through c-Jun N-terminal Kinase (JNK) Activation*

H. Cho,Y. Hwang,K. Mood,Y. Ji,Junghwa Lim,D. Morrison,I. Daar

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: EphrinB1 affects cell adhesion and migration in vitro and in vivo. Results: CNK1 interacts with ephrinB1 in cancer cell lines, and the presence of CNK1 is required for RhoA-mediated JNK activation and cell migration. Conclusion: CNK1 mediates ephrinB1 signaling that promotes cell migration through RhoA and JNK activity. Significance: CNK1 scaffold links ephrinB1 signaling to JNK activation. The Eph receptors and their membrane-bound ligands, ephrins, play important roles in various biological processes such as cell adhesion and movement. The transmembrane ephrinBs transduce reverse signaling in a tyrosine phosphorylation-dependent or -independent, as well as PDZ-dependent manner. Here, we show that ephrinB1 interacts with Connector Enhancer of KSR1 (CNK1) in an EphB receptor-independent manner. In cultured cells, cotransfection of ephrinB1 with CNK1 increases JNK phosphorylation. EphrinB1/CNK1-mediated JNK activation is reduced by overexpression of dominant-negative RhoA. Overexpression of CNK1 alone is sufficient for activation of RhoA; however, both ephrinB1 and CNK1 are required for JNK phosphorylation. Co-immunoprecipitation data showed that ephrinB1 and CNK1 act as scaffold proteins that connect RhoA and JNK signaling components, such as p115RhoGEF and MKK4. Furthermore, adhesion to fibronectin or active Src overexpression increases ephrinB1/CNK1 binding, whereas blocking Src activity by a pharmacological inhibitor decreases not only ephrinB1/CNK1 binding, but also JNK activation. EphrinB1 overexpression increases cell motility, however, CNK1 depletion by siRNA abrogates ephrinB1-mediated cell migration and JNK activation. Moreover, Rho kinase inhibitor or JNK inhibitor treatment suppresses ephrinB1-mediated cell migration. Taken together, our findings suggest that CNK1 is required for ephrinB1-induced JNK activation and cell migration.

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