By Nancy Parrish, Staff Writer
Editor's note: Platinum Highlight articles are noteworthy publications selected periodically by Dr. Craig Reynolds, associate director, National Cancer Institute, from among the most recently published Platinum Publications.
The family of proteins known as ephrins plays a critical role in a variety of biological processes. In a recent article in the Journal of Biological Chemistry, Hee Jun Cho, Ph.D., and colleagues report on the interaction between proteins CNK1 and ephrinB1 that promotes cell movement. Their findings may have an important implication in developing new therapeutics for reducing metastases in certain cancers.
“Eph and ephrin signaling has become an area of intense interest due to the influence these molecules exert on the control of cell adhesion and cell movement,” Cho said. “This signaling affects the formation of tissues during development and has been shown to play an instructive role in angiogenesis, as well as tumor cell invasion.”
Cho, a postdoctoral fellow in the Laboratory of Cell and Developmental Signaling, NCI Center for Cancer Research, said his group determined that a protein named CNK1 acts like a scaffold to mediate signaling from a cell-surface molecule called ephrinB1. EphrinB1 signaling promotes cell migration through the small GTPase protein RhoA, leading to c-Jun N-terminal kinase (JNK) activation, which is important for cell migration. “We used a combination of overexpression (gain-of-function) and knockdown of endogenous proteins (loss-of-function), along with biochemistry, to reveal the mechanism of the interaction between ephrinB1 and the CNK1 scaffold, and how this scaffold links ephrinB1 to RhoA-dependent JNK activation,” he said. The group also found that ephrinB1 and CNK1 act as scaffold proteins that connect certain RhoA and JNK signaling components, ultimately affecting cell migration.
“We believe this study reveals new mechanistic insights into how ephrinB1 signaling affects cell movement, which may have therapeutic implications during the progression of some tumors,” Cho said. “The Eph/ephrin signaling system plays a role in several morphogenetic events during development, and the de-regulation of this signaling is linked to the promotion of more aggressive and metastatic tumor phenotypes in a large variety of human cancers, including breast, lung, prostate, colon, and melanoma.”
This research will help lead to ways to prevent the interruption of normal signaling, which can lead to tumor metastasis. “The better we understand the mechanisms behind ephrinB/Eph signal transduction, the more likely we are to develop ways of inhibiting the specific cellular signals that go awry in the metastatic progression of cancers in which this system is dysregulated,” Cho said.
Cho received his doctorate in 2007 in the Department of Microbiology at Gyeongsang National University, Korea, where he first began investigating cancer metastasis and chemoresistance. He conducted studies at the Research Institute of Life Science, Gyeongsang National University, and in 2011, came to NCI at Frederick as a postdoctoral fellow in the Developmental Signal Transduction section of the Laboratory of Cell and Developmental Signaling.
Today, the focus of Cho’s research is on ephrinB1. “The elevated expression of ephrinB1 has been found in multiple cancers, such as hepatocarcinomas, gastric adenocarcinomas, and osteosarcomas, and is associated with higher metastatic potential of tumors,” he said. “I have focused my recent investigations on the possible application of a peptide derived from ephrinB1 for suppressing cancer cell migration and metastasis.”
Model for CNK1 function in ephrinB1 signaling. Adhesion to fibronectin promotes Src activation and the phosphorylation of CNK1. The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration.