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Cdc2 (red) promotes migration by phosphorylating caldesmon (green) in membrane ruffles.

Metastatic tumor cells are dangerous because they not only proliferate but also migrate and invade other tissues. On page 817, Manes et al. reach the surprising conclusion that the cyclin- dependent kinase cdc2 regulates both of these activities. The work identifies a novel signaling pathway and points to a promising new strategy for targeting metastatic cells, but it may also force a reevaluation of some current drug development efforts.

Cdc2 is well known as a cell cycle regulator, but previous work had shown that it also phosphorylates multiple cytoskeletal proteins. In the new work, the authors found that αvβ3 integrin expression in a prostate cancer cell line increases cdc2 mRNA and protein levels and leads to an increase in cdc2 kinase activity. Using cyclin B2 as a cofactor, cdc2 acts in ruffles to phosphorylate the cytoskeleton-associated protein caldesmon. Others have recently shown that this phosphorylation relieve an inhibition of actin polymerization, and thus may be pro-migratory.

The results show that, besides regulating the cell cycle, cdc2 also acts as a downstream effector of αvβ3 to regulate cell migration. This result is surprising: cdc2 is the first cyclin-dependent kinase to be linked to both migration and the cell cycle, and cyclin-dependent kinases were not known to have their expression induced by integrin expression. Manes et al. have found that the unusual dual function of cdc2 in migration and proliferation appears to be a feature of normal cells as well as tumor cells.

Because of its cell cycle function, cdc2 has been a popular target for drug developers, but its connection to two important signaling pathways suggests that cdc2 inhibitors might have wide-ranging side effects. Further dissection of the cdc2-mediated pathway regulating migration may enable the development of drugs that target only the migratory or proliferative signals mediated by cdc2, resulting in greater specificity. ▪