October 16, 2012

Molecular switches are an elegant way for a cell to regulate countless processes with a limited number of proteins. The layers of regulation that drive switch activation or inactivation allow the cell to drive one very specific process, despite the presence of all of the tools and materials to drive a thousand other processes. Today’s image is from a paper that describes one layer of regulation on a well-studied (and well-loved) set of molecular switches.

Rho GTPases are actin regulators that switch between active and inactive states. Their activation state is regulated by proteins (GEFs) that drive the GTPases into their active state, and others (GAPs) that drive them into their inactive state. RhoGDIs (Rho guanine nucleotide dissociation inhibitors) provide an additional level of control over Rho GTPase activity by sequestering Rho GTPases in inactive complexes. The selective dissociation of individual Rho GTPases from these complexes provides the cell with a context-specific response based on the actin-based structures required. A recent paper describes the function of a protein called diacylglycerol kinase ζ (DGKζ) in the release of two Rho GTPases, Rac1 and RhoA, from RhoGDI complexes. Rac1 regulates membrane ruffling and lamellipodia formation, while RhoA regulates stress fiber and focal adhesion formation. Ard and colleagues found that DGKζ-deficient cells showed signs of faulty RhoA signaling, as seen in the images above. Actin stress fibers (left column, green in merged) and focal adhesions (middle column, red in merged) appear normal in wild-type cells (top). In DGKζ-null cells (bottom row), actin stress fibers appeared condensed (arrow) and less organized, while focal adhesion distribution was impaired.

Ard, R., Mulatz, K., Abramovici, H., Maillet, J., Fottinger, A., Foley, T., Byham, M., Iqbal, T., Yoneda, A., Couchman, J., Parks, R., & Gee, S. (2012). Diacylglycerol kinase regulates RhoA activation via a kinase-independent scaffolding mechanism Molecular Biology of the Cell, 23 (20), 4008-4019 DOI: 10.1091/mbc.E12-01-0026