Ubiquitin-dependent control of Kinase Suppressor of Ras 1 (KSR1) signaling by the RING ligase praja2.

Kinase Suppressor of Ras 1 (KSR1) is an evolutionally conserved protein kinase that plays a fundamental role in mitogenic pathway. In response to Ras activation, KSR1 assembles a tripartite kinase complex that optimally transfers signals generated at cell membrane to downstream ERK signaling. The role of KSR1 in Ras signaling has been largely explored. However, the impact of attenuating signals on KSR1 was still elusive. Here, I contributed to identify a novel mechanism of ERK attenuation based on the ubiquitin-dependent control of KSR1. Stimulation of membrane receptors by growth factor induced a rapid poly-ubiquitination of KSR1, which paralleled the decay of ERK signaling. We identified praja2 as the principal E3 ligase that ubiquitinates KSR1. Interfering with praja2 expression or activity impeded KSR1 ubiquitination and sustained ERK signaling. Thus, the dynamic interplay between the ubiquitin system and scaffold components of the Ras pathway contributes to shape the profile of ERK signaling, profoundly impacting on fundamental aspects of cell behavior.