Proteins of the ubiquitin system in the Shoc2 ‐ ERK1/2 signaling axis and Noonan‐like syndrome with loose anagen hair (NSLAH) RASopathy

Abstract

The ERK1/2 signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms, i.e. RASopathies. The core ERK1/2 cascade relies on scaffold proteins such as Shoc2 to guide and fine‐tune its signals. Mutations in shoc2 lead to the development of the pathology termed Noonan‐like Syndrome with Loose Anagen Hair (NSLAH) RASopathy. However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear.We found that Shoc2 assembles an elegant multi‐component complex that incorporates several proteins of the ubiquitin system. To fine‐tune the amplitude of ERK1/2 signal transmitted via the complex, Shoc2 tethers the E3 ligase HUWE1, the (AAA+) ATPases, PSMC5 and VCP/p97, and the deubiquitinating enzyme, USP7. All of these enzymes are integral to the intricate feedback mechanism.Our recent studies demonstrated that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin‐specific protease USP7. We identified that in the Shoc2 module, USP7 functions as a molecular “switch” that controls the E3 ligase HUWE1 and the HUWE1‐induced regulatory feedback loop. We also found that disruption of Shoc2‐USP7 binding leads to aberrant activation of the Shoc2‐ERK1/2 axis. The zebrafish vertebrate model was then used to show that Shoc2 congenital mutations affecting Shoc2 interaction with USP7 lead to aberrant Shoc2 ubiquitination and signal transmission. Thus, our studies reveal a role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin‐specific proteases regulate intracellular signaling.In summary, our studies are the first to demonstrate that the Shoc2 scaffold employs multi‐protein enzymatic machinery to govern the amplitude of Shoc2‐ERK1/2 signals. We also uncover novel molecular mechanisms underlying the pathogenesis of Noonan‐like syndrome with loose anagen hair. Overall, these studies significantly advance our understanding of the mechanisms by which non‐enzymatic scaffolds regulate the specificity and dynamics of the ERK1/2 signaling networks.