uPAR's signaling two step

uPAR's signaling two step T he uPA receptor (uPAR) is a loner. Jutting from the plasma membrane , it has no apparent connection to the cell interior. But, as Madsen et al. demonstrate on page 927, uPAR induces cells to cling tightly to a surface. The behavior might recruit other receptors and explain how the seemingly isolated uPAR exerts its infl uence. Stimulating uPAR galvanizes cells—they attach to a surface, fl atten, move, and divide. Cancer cells exploit the receptor's power by cranking up its expression. But based on its structure, uPAR seems like a signaling dead end, and researchers had assumed that uPAR handed off its messages by binding to integrins. Madsen et al. tested that idea by replacing every amino acid in the receptor one at a time with alanine. They found that cells showed the typical response to uPAR stimulation unless the alanine swap meddled with the receptor segments that bind to vitronectin, a protein in the extracellular matrix. Tampering with uPAR's integrin-binding sites had no impact. To show that attachment to vitronectin was suffi cient for message transmission, the researchers modifi ed cells to make a composite protein. One end sported the membrane-anchoring portion of uPAR, and the other end carried the vitronectin-recognizing stretch of an unrelated matrix-binding protein. The hybrid protein sparked the same effects as uPAR. Together, the results show that lateral interactions between integrins and uPAR aren't essential for relaying signals to the inside of the cell. Integrins still take part in communication, however. Cells grown on a form of vitronectin that lacked an integrin-binding site ignored uPAR stimulation. Madsen et al. conclude that uPAR signaling occurs in two steps. The receptor fi rst latches onto vitronectin, spurring the cell to snuggle up to the surface. This close contact then promotes liaisons between vitronectin and integrins, which send the messages on their way. T he tactic that the protein Merlin uses to prevent tumors isn't magical, but it is unique, as Curto et al. report on page 893. The protein locks up a growth-inducing receptor in the membrane so that it can't broadcast its signals. The results suggest a possible way to combat some hard-to-treat cancers. Like its mythological namesake, Merlin is powerful and mysterious. Its gene, NF2, goes awry in several cancers. But researchers didn't know how Merlin checks cell proliferation. Some evidence pointed to an interaction with the epidermal growth factor …