Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

Abstract

The scaffold protein Shoc2 accelerates activity of the ERK1/2 pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitination of Shoc2 and its signaling partner RAF-1. Here we provide a mechanistic basis of how ubiquitination of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes PSMC5 displaces the E3-ligase HUWE1 from the scaffolding complex to attenuate ubiquitination of Shoc2 and RAF-1. We show that a Rasopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitination due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a novel critical player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner.