ERK MAP kinases disrupt the interaction between lamin A and the retinoblastoma (Rb) protein to drive cell proliferation, Rodríguez et al. report.
In response to growth factors, active ERKs enter the nucleus and stimulate cell cycle entry and progression by several different mechanisms. One of ERK's earliest actions is to bind lamin A at the nuclear periphery, where it phosphorylates and releases the transcription factor c-Fos. Rodríguez et al. noticed that the ERK-binding site on lamin A overlapped with the binding site for the Rb tumor suppressor, which inhibits cell cycle entry by sequestering the E2F family of transcription factors.
Both ERK1 and ERK2 competed with Rb for binding to lamin A, the team found, and displaced the tumor suppressor into the nucleoplasm, where it was phosphorylated and inactivated. ERKs lacking kinase activity could also dislodge and switch off Rb if they were constitutively targeted to the nucleus by a nuclear localization signal. Displacement of Rb by ERK led to increased cell proliferation and enhanced transformation, effects that were reversed by overexpressing lamin A.
Senior author Piero Crespo now wants to identify the kinase responsible for inactivating Rb once the tumor suppressor has been evicted from its binding site at the nuclear envelope. Rb is known to be phosphorylated by cyclin-dependent kinases 2, 4, and 6, but these kinases are still inactive when ERK first arrives in the nucleus to stimulate cell cycle entry. Crespo also wants to determine whether any disease-related mutations in lamin A dysregulate the cell cycle by disrupting the protein's interactions with Rb or ERKs.