Defne Yarar

Special Fellow, Whitehead Institute and MIT Center for Cancer Research 617-324-3854 phone yarar@wi.mit.edu

Among your body’s proteins, actin is a workhorse, and it seems to be everywhere. The protein is strung into microfilaments that are used in cell structure, cell movement, cell division, and muscle contraction.

Actin is also a key player in endocytosis, the primary mechanism by which cells ingest nutrients and other macromolecules. This role was first demonstrated in mammalian cells by Defne Yarar.

Yarar began working with actin as a graduate student at the University of California/Berkeley. She investigated 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.

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 researcher and then as a senior fellow 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 continues 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 is utilizing 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.

Selected Publications

Neal M. Alto, Andrew W. Weflen*, Matthew J. Rardin*, Defne Yarar*, Cheri S. Lazar, Raffi Tonikian, Charles Boone, Sachdev S. Sidhu, Sandra L. Schmid, Gail A. Hecht, Jack E. Dixon.  “The Type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways.”  Journal of Cell Biology. (2007) 178:1265-78.
         * - authors contributed equally to this work.

Defne Yarar, Clare Waterman-Storer, and Sandra L. Schmid.  “SNX9 couples actin assembly to phosphoinositide signals and is required for membrane remodeling during endocytosis.” Dev. Cell. (2007) 13(1):43-56.

Defne Yarar and Sandra L. Schmid.  “Endocytosis and Actin Dynamics in Mammalian Cells.”  The Brush Border Membrane: From Molecular Cell Biology to Clinical Pathology.  SPS. (2006) 51-65.

Fabienne Soulet, Defne Yarar, Marilyn Leonard, and Sandra L. Schmid.  “SNX9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis.” Molecular Biology of the Cell. (2005) 16(4):2058-67.

Defne Yarar, Clare Waterman-Storer, and Sandra L. Schmid.  “A Dynamic Actin Cytoskeleton Functions at Multiple Stages of Clathrin-mediated Endocytosis.” Molecular Biology of the Cell. (2005) 16(2):964-75.

[publications (pubmed database)]