It pays to have a back-up project in case your main research stalls. That's what Alan Hall (now at University College London) and colleagues learned when they set aside their studies on the protein ras and switched to its cousin rho. Their work (starting with Paterson et al., 1990) revealed that rho and related proteins were key regulators of the cell's actin cytoskeleton, and it set the stage for experiments that implicated the protein family in everything from cell cycle control to contraction of arteries.
Anne Ridley and Alan Hall find that rho and its relatives control actin dynamics.
Hall's team had been struggling to decipher the function of the oncogene ras by injecting its protein into cultured cells. Newly available recombinant rho allowed them to apply the same technique to investigate rho's impact. Post-doc Pascal Madaule of Columbia University (New York, NY) had stumbled on rho in 1985 while searching for the snail version of human chorionic gonadotrophin, and “we had no indication of what it might do,” recalls Hall.
The protein flips between a GTP-bearing active state and a GDP-carrying inactive form, and the researchers observed that injecting an always-on mutant of rho caused the cell body to compress (Paterson et al., 1990) and the actin cytoskeleton to crumple. However, the collapse only occurred if the cells were spaced out on the substrate. If the cells were packed together, activated (mutant) rho prodded them to build actin filaments. The researchers concluded that rho somehow governed the organization of the actin cytoskeleton.
To explore how, Hall and post-doc Anne Ridley starved fibroblasts of serum, thereby denying them growth factors and causing the actin filaments to dwindle. Tickling the cells with growth factors restored the fibers, but only if the cells carried working rho (Ridley and Hall, 1992). The researchers also showed that rac, another rho relative, controls actin fibers that shape the border of the cell (Ridley et al., 1992). Overall, these and other studies indicate that rho and kindred proteins, such as rac and Cdc42, link cell surface receptors to the cytoskeleton, says Hall.
But the rho family does much more. By managing the construction and destruction of actin filaments, the proteins regulate cell migration (Ridley, 2001). Rho and Cdc42 control formation of the contractile ring that separates cells during cytokinesis (Ridley, 1995). Family members help set up cell polarity (Adams et al., 1990; Gotta et al., 2001; Kay and Hunter, 2001) and push cells to advance through the cell cycle (Olson et al., 1995). In the developing nervous system, rho proteins fine-tune growth of dendrites (Lee et al., 2000) and drive differentiation of axons (Ozdinler and Erzurumlu, 2001). And in epithelial tissues, they aid the sealing of wounds (Russo, et al., 2005).