The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair

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. 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). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We identify 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 demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.

Shoc2 controls ERK1/2-driven neural crest development by balancing components of the extracellular matrix

“…The efficacy of the shoc2 MO to interfere with the translation of shoc2 mRNA was validated by Western blot analysis using an anti-Shoc2 antibody. The results of these experiments were analogous to what we reported earlier (Wilson et al, 2021) ( Fig. S1B ).…”

“…25µg of total lysate per sample was run on a 10% acrylamide gel. Western blot analysis was performed as described previously (Wilson et al, 2021). Quantification was performed using the densitometry analysis mode of Image Lab software (Bio-Rad, CA).…”

“…This protein machinery facilities the amplification of intracellular signals transmitted via the Shoc2 module. It also provides a negative feedback mechanism to fine-tune the transient Shoc2-mediated signals (Jang et al, 2014, Jang et al, 2019a, Wilson et al, 2021, Jang et al, 2015). Yet, the question of what biological activities are regulated by the Shoc2-transmitted signals remains elusive.…”

The seventh international RASopathies symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

“…USP7 plays a central role in the regulation of this complex, by promoting the inactivation of MAPK signaling. SHOC2 mutations, which have been described in individuals with NSLAH, disrupt the interaction with USP7, resulting in enhanced MAPK signaling (Wilson et al, 2021). Caitlin Chang, MD, presented a series of clinical cases of patients that had been diagnosed with mosaic RASopathies driven by KRAS mutations.…”

“…USP7 plays a central role in the regulation of this complex, by promoting the inactivation of MAPK signaling. SHOC2 mutations, which have been described in individuals with NSLAH, disrupt the interaction with USP7, resulting in enhanced MAPK signaling (Wilson et al, 2021).…”