CDK5 opens the way for DLC1

Macrophages show neutrophils the exit T auzin et al. describe how macrophages resolve infl ammation by inducing neutrophils to leave wounded tissue. Zebrafi sh neutrophils are attracted to wounds by reactive oxygen species (ROS) that activate the Src family kinase Lyn. Neutrophil-mediated infl ammation is partly resolved by apoptosis and the cells' subsequent engulfment by macrophages. But neutrophils can also elect to leave wounded tissue in a process known as reverse migration. Whether macrophages promote this mode of infl ammation resolution is unknown. Tauzin et al. found that neutrophils were generally recruited to wounds before macrophages, but, once they arrived, macrophages often contacted neutrophils and appeared to shepherd them away from the damaged tissue. Neutrophils remained in wounds for longer times in zebrafi sh larvae lacking macrophages, the researchers discovered. Like neutrophils, macrophages were attracted to wounds by ROS and Src family kinase signaling. Macrophages lacking the p22phox subunit of NADPH oxidase complex 2 (Nox2) or the tyrosine kinase Yrk were unable to migrate into wounds and induce the departure of neutrophils. Mutations in the human homologue of NOX2 cause chronic granulomatous disease, one symptom of which is enhanced neu-trophil-mediated infl ammation. Tauzin et al.'s fi ndings suggest that this may be due to defects in macrophage recruitment and the induction of neutrophil reverse migration. Senior author Anna Hut-tenlocher now wants to investigate how macrophages drive neutro-phils out of wounded tissue. She thinks the process may involve a combination of contact repulsion and chemokine signaling. CDK5 opens the way for DLC1 T ripathi et al. describe how the kinase CDK5 promotes the activity and correct localization of the tumor suppressor DLC1. DLC1 is down-regulated in a wide variety of tumors. The protein localizes to focal adhesions and contains a C-terminal GAP domain that inac-tivates Rho GTPases. How DLC1's localization and activity are regulated is unknown, however. Tripathi et al. discovered that CDK5 phosphorylates four serine residues in the N-terminal half of DLC1. Mutating these serines to nonphosphorylatable alanine residues inhibited DLC1's ability to inactivate Rho and prevented the tumor suppressor's localization to focal adhesions by inhibiting its interactions with the adhesion proteins talin and tensin. CDK5 phosphorylation disrupted an interaction between DLC1's N-terminal and GAP domains, suggesting that the kinase activates DLC1 by inducing its transition from a closed to an open conformation. Blocking this activation step reduced DLC1's tumor suppressor functions; unlike the wild-type protein, nonphosphor-ylatable DLC1 was unable …