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.

中文翻译：

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USP7 在 Shoc2-ERK1/2 信号轴和 Noonan-like 综合征中的作用与松散的生长期头发。

ERK1/2（也分别称为 MAPK3 和 MAPK1）信号通路在有机体发育和组织形态发生中至关重要。该通路的失调会导致先天性异常和严重的发育畸形。核心 ERK1/2 级联依赖支架蛋白，例如 Shoc2 来引导和微调其信号。SHOC2 中的突变导致称为 Noonan 样头发松散综合征 (NSLAH) 的病理学的发展。然而，Shoc2 功能的潜在机制及其对疾病进展的贡献仍不清楚。在这里，我们表明 ERK1/2 通路激活触发了 Shoc2 与泛素特异性蛋白酶 USP7 的相互作用。我们发现，在 Shoc2 模块中，USP7 起分子“开关”的作用 控制 E3 连接酶 HUWE1 和 HUWE1 诱导的调节反馈回路。我们还证明了 Shoc2-USP7 结合的中断会导致 Shoc2-ERK1/2 轴的异常激活。重要的是，我们的研究揭示了 USP7 在 NSLAH 致病机制中的可能作用，从而扩展了我们对泛素特异性蛋白酶如何调节细胞内信号传导的理解。