TY - JOUR
T1 - The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair
AU - Wilson, Patricia
AU - Abdelmoti, Lina
AU - Norcross, Rebecca
AU - Jang, Eun Ryoung
AU - Palayam, Malathy
AU - Galperin, Emilia
N1 - Publisher Copyright:
© 2021 Company of Biologists Ltd. All rights reserved.
PY - 2021/11
Y1 - 2021/11
N2 - The ERK1/2 (also known as MAPK3 and MAPK1, respectively) 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 reveal 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, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.
AB - The ERK1/2 (also known as MAPK3 and MAPK1, respectively) 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 reveal 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, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.
KW - ERK1/2
KW - HUWE1
KW - RASopathy
KW - Shoc2 scaffold
KW - USP7
UR - http://www.scopus.com/inward/record.url?scp=85120035973&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120035973&partnerID=8YFLogxK
U2 - 10.1242/jcs.258922
DO - 10.1242/jcs.258922
M3 - Article
C2 - 34553755
AN - SCOPUS:85120035973
SN - 0021-9533
VL - 134
JO - Journal of Cell Science
JF - Journal of Cell Science
IS - 21
M1 - jcs258922
ER -