Special Fellow Defne Yarar investigates actin in action

CAMBRIDGE, Mass. — Among your body’s proteins, actin is a workhorse, and it seems to be everywhere. The protein is strung into microfilaments that help to give your cells structure, allow them to move, divide them, and let your muscles contract.

Actin is also a key player in endocytosis, the primary mechanism by which cells ingest nutrients and other macromolecules. Defne Yarar, PhD, who first demonstrated this role in mammalian cells, has been appointed a Special Fellow of the Whitehead Institute and MIT Center for Cancer Research, arriving in September. Her lab space will be at the MIT Center for Cancer Research.

Yarar began by studying actin as a graduate student in the laboratory of Mathew Welch, PhD, at the University of California/Berkeley, investigating how the actin filaments that crisscross the cell—collectively known as the cytoskeleton—are regulated during cell movement.

Scientists already knew that a cell travels by extending actin filaments ahead of its leading edge. But they didn’t know the details of the polymerization process by which these filaments begin to extend themselves.

Working with purified proteins, Yarar and her colleagues showed that the Wiskott-Aldrich Syndrome protein (WASP) could stimulate the Arp2/3 protein complex, which is known to kick off filament polymerization. She further demonstrated this by coating plastic beads with WASP, placing them in a culture derived from frog eggs and examining the formation of actin filaments at the surface of the beads.

Yarar went on to study the role of the actin cytoskeleton in endocytosis, as a postdoctoral fellow and then a senior fellow in the laboratory of Sandra Schmid, PhD, at The Scripps Research Institute in La Jolla, California.

The primary route for the cellular uptake of macromolecules is a process called clathrin-mediated endocytosis, during which a structural protein called clathrin assists the cell's outer membrane in folding inward to form vesicles—small balloon-like structures, entirely enclosed by a membrane. This operation is essential for nutrient uptake, certain forms of cell regulation (such as turning off extracellular growth signals), immune system function and other crucial tasks.

Wondering whether the actin cytoskeleton also plays a role in endocytosis, Yarar completed biochemical assays indicating that the process continues even when actin polymerization has ended. Studies of live cells with a high-resolution fluorescence microscope showed, however, that loss of actin polymerization almost shuts down endocytosis. Yarar followed up with studies of how this process is regulated, pinpointing an essential role for a protein called SNX9, which aids both in remodeling the cell membrane and in driving actin filament formation.

At Whitehead, Yarar will continue to probe the mystery of actin’s precise role in endocytosis—with live cell imaging, electron microscopy and tests with drugs and genetic inhibitors. In addition, she will utilize a variety of research techniques to examine how SNX9 and other proteins regulate actin during endocytosis. “The identification of novel factors that regulate this protein during endocytosis will enable the development of assays to screen for human disease and the identification of potential targets for new drug therapies,” Yarar explains.

“Defne has identified a key player in the endocytosis pathway,” comments Whitehead Member Hidde Ploegh. “That pathway is so fundamental—so important for virus entry, nutrient intake and other processes—that Whitehead can ill afford to lack expertise in endocytosis. We’re excited that Defne will be joining us to fill that need.”