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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:p>\n                    The\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    tumor suppressor gene is recurrently mutated in human cancers and is associated with the neurofibromatosis type 1 (NF-1) cancer predisposition syndrome.\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    encodes neurofibromin, a Ras guanosine triphosphate (GTPase) activating protein that negatively regulates Ras signaling.\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    (sg\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    ) repression is sufficient to increase Ras GTP levels and alter gene expression to promote cell proliferation and dedifferentiation, with sg\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    iPNs showing decreased sensitivity to selumetinib due to altered feedback regulation to Ras\/RAF\/MEK\/ERK. Upstream small guide\n                    <jats:italic toggle=\"yes\">PTPN11<\/jats:italic>\n                    (sg\n                    <jats:italic toggle=\"yes\">PTPN11<\/jats:italic>\n                    ) repression leads to the inverse gene expression signature, decreasing cell proliferation and promoting differentiation, and sg\n                    <jats:italic toggle=\"yes\">PTPN11<\/jats:italic>\n                    iPNs are more sensitive to selumetinib. However, upstream sonof sevenless 1 inhibition shows limited efficacy in iPNs due to compensation by SOS2. Finally, proximal proteomics reveals Kirsten rat sarcoma virus (KRAS), but not Harvey rat sarcoma virus (HRAS) or neuroblastoma Ras viral oncogene homolog (NRAS), associates with neurofibromin in iPN cells, and pan-KRAS inhibition is sufficient to block ERK activation and CDK1\/2 activation in\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    mutant cells, suggesting blocking KRAS may be a therapeutic approach for\n                    <jats:italic toggle=\"yes\">NF1<\/jats:italic>\n                    mutant PNS tumors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2506823122","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T15:45:31Z","timestamp":1751298331000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system"],"prefix":"10.1073","volume":"122","author":[{"given":"Harish N.","family":"Vasudevan","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Arang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California","place":["San Francisco"]},{"name":"Department of Cellular and Molecular Pharmacology, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sacconi Nunez","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Mohabeer","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California San Francisco","place":["San Francisco"]},{"name":"Department of Neurological Surgery, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Sale","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4902-337X","authenticated-orcid":false,"given":"Nevan J.","family":"Krogan","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pharmacology, Quantitative Biosciences Institute, University of California","place":["San Francisco"]},{"name":"Department of Cellular and Molecular Pharmacology, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Forget","sequence":"additional","affiliation":[{"name":"Department of 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