Led by Drs. Robert Singer and Dr Stefan Huettelmaier, the research team focused on migrating fibroblast cells important in wound healing. To move towards a wound, these cells manufacture the protein actin, which polymerizes into long filaments that push the cell's membrane outward to form protrusions.
The team's previous work showed how newly formed actin messenger RNA molecules find their way to the cell's periphery: A protein called ZBP1 binds to the messenger RNA and "escorts" it out of the fibroblast nucleus and into the cytoplasm. On reaching the cell's periphery, the messenger RNA is translated into actin protein responsible for cell motility.
This new study reveals another key role for ZBP1: Not only does ZBP1 bind to actin messenger RNA and guide it to the cell's periphery, but it also helps regulate where in the cell the messenger RNA is translated into actin.
"The ZBP1 bound to actin's messenger RNA acts like a lock to prevent it from being translated into protein before reaching its destination," explains Dr. Singer. "On arriving at the cell periphery, the messenger RNA/ZBP1 complex encounters an enzyme, the protein kinase Src, which is active only in that part of the cell. Src adds a phosphate group to ZBP1 close to where it binds to messenger RNA, and this phosphorylation reaction detaches ZBP1 from the actin messenger RNA--unlocking the messenger RNA so it can now be translated into the actin protein that makes cell movement possible."
Understanding how actin synthesis is spatially regulated in motile cells could lead to new cancer therapies. "In cancer," says Dr. Singer, "we know that expression of ZBP1 correlates with benign tumors, while suppression of ZBP1 is associated with metastasis--when motile cancer cells break off from the primary tumor and invade other areas of the body. So a drug that could force tumor cells to express ZBP1 might prevent cancers from spreading."
In addition to Dr. Singer, other Einstein researchers involved in the study are Dr. John Condeelis, professor and co-chair with Dr. Singer of Einstein's Department of Anatomy and Structural Biology, Daniel Zenklusen, Mike Lorenz, XiuHua Meng, and Jason Dictenberg of that department, Gary J. Bassell of the Department of Neuroscience at Einstein, and Dr. Marcell Lederer, now in Dr. Huettelmaier's laboratory of Martin-Luther-University of Halle, Germany.