A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system

作者：Harish N. Vasudevan, Nadia Arang, Maria Sacconi Nunez, Patrick Kennedy, Emily Payne, Sarah Mohabeer, Julian Chien, Aaron Wright, Matthew J. Sale, Nevan J. Krogan, Antoine Forget, Frank McCormick · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2506823122 · 被引用次数：1 · 研究领域：Neurofibromatosis and Schwannoma Cases、Protein Tyrosine Phosphatases、Neuroblastoma Research and Treatments

The NF1 tumor suppressor gene is recurrently mutated in human cancers and is associated with the neurofibromatosis type 1 (NF-1) cancer predisposition syndrome. NF1 encodes neurofibromin, a Ras guanosine triphosphate (GTPase) activating protein that negatively regulates Ras signaling. NF1 mutation accordingly leads to Ras misactivation and downstream activation of RAF/MEK/ERK signaling, leading to the approval of the MEK inhibitor selumetinib for NF-1 associated peripheral nervous system (PNS) tumors. However, how NF1 loss modifies response to selumetinib and the utility of targeting additional upstream inputs or downstream outputs of Ras these tumors remain unclear. Here, we perform RNA-sequencing, phosphoproteomic, pharmacologic, and proximal proteomic analysis across a panel of CRISPR interference immortalized peripheral nerve (iPN) cells to systematically dissect the function of neurofibromin loss. Small guide NF1 (sg NF1 ) repression is sufficient to increase Ras GTP levels and alter gene expression to promote cell proliferation and dedifferentiation, with sg NF1 iPNs showing decreased sensitivity to selumetinib due to altered feedback regulation to Ras/RAF/MEK/ERK. Upstream small guide PTPN11 (sg PTPN11 ) repression leads to the inverse gene expression signature, decreasing cell proliferation and promoting differentiation, and sg PTPN11 iPNs are more sensitive to selumetinib. However, upstream sonof sevenless 1 inhibition shows limited efficacy in iPNs due to compensati...